Identification of potentially actionable genetic variants in epithelial ovarian cancer: a retrospective cohort study.

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.

Sexual health in Belgian cervical cancer survivors: an exploratory qualitative study.

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.

Vaginal morbidity, sexual functioning, and health-related quality of life in cervical cancer survivors: a cross-sectional multicenter study (VAMOS).

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.

Pembrolizumab, radiotherapy, and an immunomodulatory five-drug cocktail in pretreated patients with persistent, recurrent, or metastatic cervical or endometrial carcinoma: Results of the phase II PRIMMO study.

A phase II study (PRIMMO) of patients with pretreated persistent/recurrent/metastatic cervical or endometrial cancer is presented. Patients received an immunomodulatory five-drug cocktail (IDC) consisting of low-dose cyclophosphamide, aspirin, lansoprazole, vitamin D, and curcumin starting 2 weeks before radioimmunotherapy. Pembrolizumab was administered three-weekly from day 15 onwards; one of the tumor lesions was irradiated (8Gyx3) on days 15, 17, and 19. The primary endpoint was the objective response rate per immune-related response criteria (irORR) at week 26 (a lower bound of the 90% confidence interval [CI] of > 10% was considered efficacious). The prespecified 43 patients (cervical, n = 18; endometrial, n = 25) were enrolled. The irORR was 11.1% (90% CI 2.0-31.0) in cervical cancer and 12.0% (90% CI 3.4-28.2) in endometrial cancer. Median duration of response was not reached in both cohorts. Median interval-censored progression-free survival was 4.1 weeks (95% CI 4.1-25.7) in cervical cancer and 3.6 weeks (95% CI 3.6-15.4) in endometrial cancer; median overall survival was 39.6 weeks (95% CI 15.0-67.0) and 37.4 weeks (95% CI 19.0-50.3), respectively. Grade ≥ 3 treatment-related adverse events were reported in 10 (55.6%) cervical cancer patients and 9 (36.0%) endometrial cancer patients. Health-related quality of life was generally stable over time. Responders had a significantly higher proportion of peripheral T cells when compared to nonresponders (p = 0.013). In conclusion, PRIMMO did not meet its primary objective in both cohorts; pembrolizumab, radiotherapy, and an IDC had modest but durable antitumor activity with acceptable but not negligible toxicity.Trial registration ClinicalTrials.gov (identifier NCT03192059) and EudraCT Registry (number 2016-001569-97).

Mental Health and Quality of Life among Patients with Cancer during the SARS-CoV-2 Pandemic: Results from the Longitudinal ONCOVID Survey Study.

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.

Risk of Thrombo-Embolic Events in Ovarian Cancer: Does Bevacizumab Tilt the Scale? A Systematic Review and Meta-Analysis.

Thromboembolic events are the second cause of death in cancer patients. In ovarian cancer, 3-10% of patients present with venous thromboembolism (VTE), but the incidence may rise to 36% along the disease course. Bevacizumab is a monoclonal antibody directed against vascular endothelial-derived growth factor, and in in vitro studies it showed a predisposition to hemostasis perturbation, including thrombosis. However, in vivo and clinical studies have shown conflicting results for its use as a treatment for ovarian cancer, so we conducted a systematic review and meta-analysis on the risk of arterial thromboembolism (ATE) and VTE in ovarian cancer patients treated with bevacizumab. The review comprised 14 trials with 6221 patients: ATE incidence was reported in 5 (4811 patients) where the absolute risk was 2.4% with bevacizumab vs. 1.1% without (RR 2.45; 95% CI 1.27-4.27, p = 0.008). VTE incidence was reported in 9 trials (5121 patients) where the absolute risk was 5.4% with bevacizumab vs. 3.7% without (RR 1.32; 95% CI 1.02-1.79, p = 0.04). Our analysis showed that the risk of arterial and venous thromboembolism increased in patients treated with bevacizumab. Thrombolic events (TEs) are probably underreported, and studies should discriminate between ATE and VTE. Bevacizumab can be considered as an additional risk factor when selecting patients for primary prophylaxis with anticoagulants.

Splenic Hematopoietic and Stromal Cells in Cancer Progression.

Tumor-derived secretory factors orchestrate splenic hematopoietic and stromal cells to fuel metastasis. The spleen acts as a reservoir site for hematopoietic stem and progenitor cells, which are rapidly exploited as myeloid-derived suppressor cells at the cost of tumor-reactive lymphoid cells. Splenic erythroid progenitor cells and mesenchymal stromal cells contribute directly and indirectly to both tumor immune escape and the metastatic cascade. Animal models provide valuable mechanistic insights, but their translation to a clinical setting highlights specific challenges and open issues. In this review, we envision the exploitation of the spleen as a source for novel biomarkers and therapeutic approaches.

Splenic 18F-FDG uptake on baseline PET/CT is associated with oncological outcomes and tumor immune state in uterine cervical cancer.

OBJECTIVE: The spleen represents an important contributor to tumor immune escape, but the relevance of increased splenic metabolic activity remains to be fully elucidated. METHODS: We retrospectively measured the spleen-to-liver standard uptake value (SLR) on 18F-FDG PET/CT examinations of 92 consecutive patients with FIGO stage IB1 to IVA cervical cancer and integrated the results with survival, response to treatment, tumor immune infiltrate, and baseline characteristics. RESULTS: SLRmax > 0.92 (p = .026) and SLRmean > 0.94 (p = .005) were significantly associated with decreased DFS in univariable analysis. Multivariable models were built using best subset selection; ΔSLRmax and either SLRmax or SLRmean were consistently selected, strongly reinforcing the association between SLR variables and DFS in relation to potential confounders (all models p ≤ .002). Independent associations were found for SLRmax using multivariable Cox regression models for DFS (all p ≤ .003). Further, uni- and multivariable analyses demonstrated the negative impact of higher SLR values on pathological complete response. A statistically significant higher proportion of patients with high SLRmax had a dense infiltrate of CD20+ (p = .036) and CD68+ (p = .015) immune cells, as well as PD-L1+ tumor cells (p = .019) as compared to those with low SLRmax. Finally, high SLRmax status was neither associated with systemic inflammatory markers (except for an increased white blood cell count; p = .038), nor with clinically overt infection. CONCLUSION: This hypothesis-generating study provides the first evidence that increased splenic metabolic activity is a negative prognostic and predictive biomarker in locally advanced cervical cancer. In addition, it might help to discriminate immunologically 'hot' from 'cold' cervical tumors.

The nocebo effect and tobacco control-First, do no harm?

Since tobacco remains a leading cause of global morbidity and mortality, emphasis needs to be given to preventive approaches to tobacco consumption. Environmental and policy strategies with fear appeals are important contributors to reductions in smoking prevalence. Fear appeals are persuasive messages-often using graphic and emotionally evocative imagery and language-that attempt to scare their audiences into tobacco cessation. While the intentions of fear appeals are benign, their effects are not necessarily so; here, we argue that some fear appeals carry a significant risk of backfiring by eliciting nocebo effects among its viewers. In this context, it is important to recognize that there is currently no justification for disregarding potential nocebo effects. Therefore, we should improve our understanding of nocebo effects in the field of preventive medicine, as well as the impact of strategies aimed at mitigating their negative health effects.

Immunologic impact of chemoradiation in cervical cancer and how immune cell infiltration could lead toward personalized treatment.

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.

Fibroblasts Fuel Immune Escape in the Tumor Microenvironment.

Immune escape is central to the persistence of most, if not all, solid tumors and poses a critical obstacle to successful cancer (immuno)therapy. Cancer-associated fibroblasts (CAFs) constitute the most prevalent, yet heterogeneous, component of the tumor stroma, where they 'cool down' the immune microenvironment. The central role played by CAFs, both as a physical barrier and source of immunosuppressive molecules, sets them as a target to enhance immunotherapy of cancer. We outline the current understanding of how CAFs fuel immune escape, as well as their potential clinical applications. Whether these therapeutics really have clinically significant activity remains to be seen, but the outlook is positive.