Distinct Genomic Profiles Are Associated with Treatment Response and Survival in Ovarian Cancer

SIMPLE SUMMARY: In most patients with ovarian cancer, their disease eventually becomes resistant to chemotherapy. The timing and type of treatment given are therefore highly important. Currently, treatment choice is mainly based on the subtype of cancer (from a histological point of view), prior response to chemotherapy, and the time it takes for the disease to recur. In this study, we combined complete genome data of the tumor with clinical data to better understand treatment responses. In total, 132 tumor samples were included, all from patients with disease that had spread beyond the primary location. By clustering the samples based on genetic characteristics, we have identified subgroups with distinct response rates and survival outcomes. We suggest that in the future, this data can be used to make more informed treatment choices for individuals with ovarian cancer. ABSTRACT: The majority of patients with ovarian cancer ultimately develop recurrent chemotherapy-resistant disease. Treatment stratification is mainly based on histological subtype and stage, prior response to platinum-based chemotherapy, and time to recurrent disease. Here, we integrated clinical treatment, treatment response, and survival data with whole-genome sequencing profiles of 132 solid tumor biopsies of metastatic epithelial ovarian cancer to explore genome-informed stratification opportunities. Samples from primary and recurrent disease harbored comparable numbers of single nucleotide variants and structural variants. Mutational signatures represented platinum exposure, homologous recombination deficiency, and aging. Unsupervised hierarchical clustering based on genomic input data identified specific ovarian cancer subgroups, characterized by homologous recombination deficiency, genome stability, and duplications. The clusters exhibited distinct response rates and survival probabilities which could thus potentially be used for genome-informed therapy stratification for more personalized ovarian cancer treatment

The association between patient satisfaction with information and adherence to oral anticancer agents

INTRODUCTION: Adherence to anticancer agents is a critical factor in achieving adequate clinical response, and became a major challenge for patients and caregivers since the increased substitution of parenteral cytostatic by oral drugs. One of the factors that influences adherence is how well informed patients are about their therapy. This study assesses the association between patient satisfaction with information about oral anticancer agents and adherence. MATERIALS AND METHODS: This study was conducted among patients (≥18 years) who began oral anticancer therapy. Patients satisfaction with information and adherence were assessed using validated questionnaires. Adherence was also assessed using refill data. Logistic regression was applied to assess the association between overall patient satisfaction with information and both self-reported adherence and adherence based on an MPR value of above 80%. RESULTS: In total, 124 patients were included in the study. The median (IQR) satisfaction with information was 15.0(4) on a scale of 0-17. Eighty-two percent of participants reported adherence, while the refill data demonstrated that 64.5% of patients had an adherence rate of 80% or higher. Overall satisfaction with information was not significantly associated with self-reported adherence (OR adj 0.98 [95% CI 0.85-1.15]) or refill-based adherence (OR adj 1.11 [95% CI 0.99-1.24]). CONCLUSION: The findings indicate no significant relationship between patient satisfaction with information and adherence. The population was highly satisfied with information about the oral anticancer agents, which indicates a high level of satisfaction with usual care. However, the refill data reveals that 35.5% of patients were not adherent

Whole Genome Analysis of Ovarian Granulosa Cell Tumors Reveals Tumor Heterogeneity and a High-Grade TP53-Specific Subgroup

Adult granulosa cell tumors (AGCTs) harbor a somatic FOXL2 c.402C>G mutation in ~95% of cases and are mainly surgically removed due to limited systemic treatment effect. In this study, potentially targetable genomic alterations in AGCTs were investigated by whole genome sequencing on 46 tumor samples and matched normal DNA. Copy number variant (CNV) analysis confirmed gain of chromosome 12 and 14, and loss of 22. Pathogenic TP53 mutations were identified in three patients with highest tumor mutational burden and mitotic activity, defining a high-grade AGCT subgroup. Within-patient tumor comparisons showed 29–80% unique somatic mutations per sample, suggesting tumor heterogeneity. A higher mutational burden was found in recurrent tumors, as compared to primary AGCTs. FOXL2-wildtype AGCTs harbored DICER1, TERT(C228T) and TP53 mutations and similar CNV profiles as FOXL2-mutant tumors. Our study confirms that absence of the FOXL2 c.402C>G mutation does not exclude AGCT diagnosis. The lack of overlapping variants in targetable cancer genes indicates the need for personalized treatment for AGCT patients

In Vitro Systematic Drug Testing Reveals Carboplatin, Paclitaxel, and Alpelisib as a Potential Novel Combination Treatment for Adult Granulosa Cell Tumors

Simple Summary: Granulosa cell tumor treatment is challenging as there are few effective options besides surgery. In this study, we obtained tumor tissue from patients at surgery and cultured tumor cells in the laboratory. After sufficient expansion, we tested the effects of current treatments, such as chemotherapy and anti-hormonal treatment, and novel anti-cancer treatment options on cell survival. Results were generated within three weeks after tissue collection. We found that all drugs were ineffective when used as single treatments; however, some combinations were very effective. The PI3K protein inhibitor alpelisib was effective in combination with chemotherapy and achieved 50% cell death at assumed tolerable patient plasma concentrations. In conclusion, this study shows an approach to rapidly establish patient-derived cell lines for drug screens. The effectiveness of combined treatment with alpelisib and chemotherapy in granulosa cell tumors should be further investigated and may be a promising novel treatment option in patients with a granulosa cell tumor. Adult granulosa cell tumors (AGCTs) arise from the estrogen-producing granulosa cells. Treatment of recurrence remains a clinical challenge, as systemic anti-hormonal treatment or chemotherapy is only effective in selected patients. We established a method to rapidly screen for drug responses in vitro using direct patient-derived cell lines in order to optimize treatment selection. The response to 11 monotherapies and 12 combination therapies, including chemotherapeutic, anti-hormonal, and targeted agents, were tested in 12 AGCT-patient-derived cell lines and an AGCT cell line (KGN). Drug screens were performed within 3 weeks after tissue collection by measurement of cell viability 72 h after drug application. The potential synergy of drug combinations was assessed. The human maximum drug plasma concentration (Cmax) and steady state (Css) thresholds obtained from available phase I/II clinical trials were used to predict potential toxicity in patients. Patient-derived AGCT cell lines demonstrated resistance to all monotherapies. All cell lines showed synergistic growth inhibition by combination treatment with carboplatin, paclitaxel, and alpelisib at a concentration needed to obtain 50% cell death (IC50) that are below the maximum achievable concentration in patients (IC50 <Cmax). We show that AGCT cell lines can be rapidly established and used for patient-specific in vitro drug testing, which may guide treatment decisions. Combination treatment with carboplatin, paclitaxel, and alpelisib was consistently effective in AGCT cell lines and should be further studied as a potential effective combination for AGCT treatment in patients

Gastric cancer during pregnancy: A report on 13 cases and review of the literature with focus on chemotherapy during pregnancy

Introduction: Gastric cancer during pregnancy is extremely rare and data on optimal treatment and possible chemotherapeutic regimens are scarce. The aim of this study is to describe the obstetric and maternal outcome of women with gastric cancer during pregnancy and review the literature on antenatal chemotherapy for gastric cancer. Material and methods: Treatment and outcome of patients registered in the International Network on Cancer, Infertility and Pregnancy database with gastric cancer diagnosed during pregnancy were analyzed. Results: In total, 13 women with gastric cancer during pregnancy were registered between 2002 and 2018. Median gestational age at diagnosis was 22 weeks (range 6-30 weeks). Twelve women were diagnosed with advanced disease and died within 2 years after pregnancy, most within 6 months. In total, 8 out of 10 live births ended in a preterm delivery because of preeclampsia, maternal deterioration, or therapy planning. Two out of 6 women who initiated chemotherapy during pregnancy delivered at term. Two neonates prenatally exposed to chemotherapy were growth restricted and 1 of them developed a systemic infection with brain abscess after preterm delivery for preeclampsia 2 weeks after chemotherapy. No malformations were reported. Conclusions: The prognosis of gastric cancer during pregnancy is poor, mainly due to advanced disease at diagnosis, emphasizing the need for early diagnosis. Antenatal chemotherapy can be considered to reach fetal maturity, taking possible complications such as growth restriction, preterm delivery, and hematopoietic suppression at birth into account

First-in-Human Phase I Study of GSK2126458, an Oral Pan-Class I Phosphatidylinositol-3-Kinase Inhibitor, in Patients with Advanced Solid Tumor Malignancies

GSK2126458 (GSK458) is a potent inhibitor of PI3K (α, β, γ, and δ), with preclinical studies demonstrating broad antitumor activity. We performed a first-in-human phase I study in patients with advanced solid tumors

Pan-cancer whole-genome analyses of metastatic solid tumours

Contains fulltext : 215492.pdf (publisher's version ) (Open Access)Metastatic cancer is a major cause of death and is associated with poor treatment efficacy. A better understanding of the characteristics of late-stage cancer is required to help adapt personalized treatments, reduce overtreatment and improve outcomes. Here we describe the largest, to our knowledge, pan-cancer study of metastatic solid tumour genomes, including whole-genome sequencing data for 2,520 pairs of tumour and normal tissue, analysed at median depths of 106x and 38x, respectively, and surveying more than 70 million somatic variants. The characteristic mutations of metastatic lesions varied widely, with mutations that reflect those of the primary tumour types, and with high rates of whole-genome duplication events (56%). Individual metastatic lesions were relatively homogeneous, with the vast majority (96%) of driver mutations being clonal and up to 80% of tumour-suppressor genes being inactivated bi-allelically by different mutational mechanisms. Although metastatic tumour genomes showed similar mutational landscape and driver genes to primary tumours, we find characteristics that could contribute to responsiveness to therapy or resistance in individual patients. We implement an approach for the review of clinically relevant associations and their potential for actionability. For 62% of patients, we identify genetic variants that may be used to stratify patients towards therapies that either have been approved or are in clinical trials. This demonstrates the importance of comprehensive genomic tumour profiling for precision medicine in cancer