Prognostic and predictive factors in patients with metastatic or recurrent cervical cancer treated with platinum-based chemotherapy.

BACKGROUND: Recognizing resistance or susceptibility to the current standard cisplatin and paclitaxel treatment could improve therapeutic outcomes of metastatic or recurrent cervical cancer. METHODS: Forty-five tissue samples from patients participating in a phase II trial of cisplatin and ifosfamide, with or without paclitaxel were collected for retrograde analysis. Immunohistochemistry and genotyping was performed to test ERCC1, III ß-tubulin, COX-2, CD4, CD8 and ERCC1 (C8092A and N118 N) and MDR1 (C3435T and G2677 T) gene polymorphisms, as possible predictive and prognostic markers. Results were statistically analyzed and correlated with patient characteristics and outcomes. RESULTS: Patients with higher levels of ERCC1 expression had shorter PFS and OS than patients with low ERCC1 expression (mPFS:5.1 vs 10.2 months, p = 0.027; mOS:10.5 vs. 21.4 months, p = 0.006). Patients with TT in the site of ERCC1 N118 N and GT in the site of MDR1 G2677 T polymorphisms had significantly longer PFS (p = 0.006 and p = 0.027 respectively). ERCC1 expression and the ERCC1 N118 N polymorphism remained independent predictors of PFS. Interestingly, high III beta tubulin expression was associated with chemotherapy resistance and fewer responses [5/20 (25%)] compared to lower III ß-tubulin expression [15/23 (65.2%)] (p = 0.008). Finally, ΙΙΙ ß-tubulin levels and chemotherapy regimen were independent predictors of response to treatment. CONCLUSIONS: ERCC1 expression proved to be a significant prognostic factor for survival in our metastatic or recurrent cervical cancer population treated with cisplatin based chemotherapy. ERCC1 N118 N and MDR1 G2677 T polymorphism also proved of prognostic significance for disease progression, while overexpression of III ß-tubulin was positively correlated with chemotherapy resistance.

The Effect of Melatonin Supplementation on Cancer-Related Fatigue during Chemotherapy Treatment of Breast Cancer Patients: A Double-Blind, Randomized Controlled Study.

Cancer-related fatigue (CRF) is a common distressing complaint of breast cancer (BC) patients treated with chemotherapy. Nutritional quality plays a pivotal role in CRF, while increased interest towards new pharmacological agents has been observed. Melatonin, an endogenous hormone that regulates the human sleep-wake cycle, could alleviate CRF. In the present randomized, placebo-controlled 3-month trial, we investigated the effects of melatonin intake (i.e., 1 mg/day) vs. placebo in BC patients on CRF. In both arms, the Mediterranean diet (MD) was implemented. Medical history, anthropometry and blood withdrawal were performed. CRF was evaluated by the Functional Assessment of Chronic Illness Therapy-Fatigue questionnaire and MD adherence by the MedDietScore. In total, 49 BC women (median age 52 years) were recruited, namely N = 23 in the intervention arm and N = 26 in the placebo arm. At baseline, CRF was positively associated with body mass index (BMI), even when adjusted for age, waist circumference and blood indices related to disease prognosis (beta = -0.882, p = 0.003). At 3 months, both groups showed a BMI decrease (p < 0.05), but only the intervention group improved CRF compared to baseline (p = 0.003). No differences in CRF were observed between the groups. In conclusion, melatonin oral supplementation could ameliorate CRF in BC patients.

Genetic Testing of Breast Cancer Patients with Very Early-Onset Breast Cancer (≤30 Years) Yields a High Rate of Germline Pathogenic Variants, Mainly in the BRCA1, TP53, and BRCA2 Genes.

Early-onset breast cancer constitutes a major criterion for genetic testing referral. Nevertheless, studies focusing on breast cancer patients (≤30 years) are limited. We investigated the contribution and spectrum of known breast-cancer-associated genes in 267 Greek women with breast cancer ≤30 years while monitoring their clinicopathological characteristics and outcomes. In this cohort, a significant proportion (39.7%) carried germline pathogenic variants (PVs) distributed in 8 genes. The majority, namely 36.7%, involved BRCA1, TP53, and BRCA2. PVs in BRCA1 were the most prevalent (28.1%), followed by TP53 (4.5%) and BRCA2 (4.1%) PVs. The contribution of PVs in CHEK2, ATM, PALB2, PTEN, and RAD51C was limited to 3%. In the patient group ≤26 years, TP53 PVs were significantly higher compared to the group 26-30 years (p = 0.0023). A total of 74.8% of TP53 carriers did not report a family history of cancer. Carriers of PVs receiving neoadjuvant chemotherapy showed an improved event-free survival (p < 0.0001) compared to non-carriers. Overall, many women with early-onset breast cancer carry clinically actionable variants, mainly in the BRCA1/2 and TP53 genes. The inclusion of timely testing of TP53 in these patients provides essential information for appropriate clinical management. This is important for countries where reimbursement involves the cost of genetic analysis of BRCA1/2 only.

Guided Imagery and Music in the Treatment for Breast and Gynecologic Cancer: An RCT Pilot.

The primary aim of this randomized controlled trial pilot was to investigate the potential effectiveness of the music psychotherapy method, Guided Imagery and Music (GIM), to assist female patients who are undergoing chemotherapy treatment for breast or gynecologic cancer. A secondary aim was to suggest performance improvements regarding the protocol and the resources required to undertake a future larger scale study. The researchers randomized participants (n = 20) into two groups: Intervention group (n = 10) and Control group (n = 10). The Intervention group received a series of six individual, short GIM sessions whereas the Control group received two verbal counseling sessions that took place at Week 1 and at Week 6 of treatment. All participants in the study completed the Profile of Mood States (POMS-Brief); Cancer Fatigue Scale (CFS); and Herth Hope Index (HHI) before the beginning of Week 1 and again after Week 6 or, in the case of the Intervention group, after the last GIM session. All participants also completed two Visual Analogue Scales (VAS-Hope; VAS-Fatigue) weekly or after each session throughout the duration of the trial. The results of the Intervention group receiving GIM showed medium pre-post effect sizes for the CFS, HHI, and POMS questionnaires, and significant positive changes for the VAS-H and VAS-F questionnaires. As seen from this initial data outcome, a brief series of GIM sessions shows promise to be beneficial for increasing hope, decreasing fatigue, and mitigating distressed mood for female patients undergoing treatment for breast or gynecologic cancer.

Concordance between Three Homologous Recombination Deficiency (HRD) Assays in Patients with High-Grade Epithelial Ovarian Cancer.

Our aim was to evaluate the concordance between the Myriad MyChoice and two alternative homologous recombination deficiency (HRD) assays (AmoyDx HRD Focus NGS Panel and OncoScan™) in patients with epithelial ovarian cancer (EOC). Tissue samples from 50 patients with newly diagnosed EOC and known Myriad MyChoice HRD status were included. DNA aliquots from tumor samples, previously evaluated with Myriad MyChoice and centrally reassessed, were distributed to laboratories to assess their HRD status using the two platforms, after being blinded for the Myriad MyChoice CDx HRD status. The primary endpoint was the concordance between Myriad MyChoice and each alternative assay. Tumor samples were evaluated with an AmoyDx® HRD Focus Panel (n = 50) and with OncoScan™ (n = 43). Both platforms provided results for all tumors. Analysis showed that correlation was high for the Myriad MyChoice GI score and AmoyDx® HRD Focus Panel (r = 0.79) or OncoScan™ (r = 0.87) (continuous variable). The overall percent agreement (OPA) between Myriad MyChoice GI status (categorical variable) and each alternative assay was 83.3% (68.6-93.3%) with AmoyDx and 77.5% (61.5-89.2%) with OncoScan™. The OPA in HRD status between Myriad MyChoice and AmoyDx was 88.6% (75.4-96.2). False-positive rates were 31.6% (6/19) for AmoyDx GI status and 31.9% (7/22) for OncoScan™, while false-negative rates were 0% (0/28, AmoyDx) and 11.1% (2/18, OncoScan™) compared with the Myriad MyChoice GI status. While substantial concordance between Myriad MyChoice and alternative assays was demonstrated, prospective validation of the analytical performance and clinical relevance of these assays is warranted.

Only 32.3% of Breast Cancer Families with Pathogenic Variants in Cancer Genes Utilized Cascade Genetic Testing.

BACKGROUND: Hereditary cancer predisposition syndromes are responsible for approximately 5-10% of all diagnosed cancer cases. In order to identify individuals at risk in a cost-efficient manner, family members of individuals carrying pathogenic alterations are tested only for the specific variant that was identified in their carrier relative. The purpose of this study was to investigate the clinical use and implementation of cascade family testing (CFT) in families of breast cancer patients with pathogenic/likely pathogenic variants (PVs/LPVs) in cancer-related predisposition genes. METHODS: Germline sequencing was carried out with NGS technology using a 52-gene panel, and cascade testing was performed by Sanger sequencing or MLPA. RESULTS: In a cohort of 1785 breast cancer patients (families), 20.3% were found to have PVs/LPVs. Specifically, 52.2%, 25.1%, and 22.7% of patients had positive findings in high-, intermediate-, and low-penetrance breast cancer susceptibility genes, respectively. Although CFT was recommended to all families, only 117 families (32.3%) agreed to proceed with genetic testing. Among the first-degree relatives who underwent CFT, 70.3% were female, and 108 of 121 (89.3%) were cancer free. Additionally, 42.7%, 36.7%, and 20.6% were offspring, siblings, and parents of the subject, respectively. Our data suggest that CFT was mostly undertaken (104/117, 88.8%) in families with positive findings in high-risk genes. CONCLUSIONS: Cascade family testing can be a powerful tool for primary cancer prevention by identifying at-risk family members. It is of utmost importance to implement genetic counseling approaches leading to increased awareness and communication of genetic testing results.

Copy Number Variations (CNVs) Account for 10.8% of Pathogenic Variants in Patients Referred for Hereditary Cancer Testing.

BACKGROUND/AIM: Germline copy number variation (CNV) is a type of genetic variant that predisposes significantly to inherited cancers. Today, next-generation sequencing (NGS) technologies have contributed to multi gene panel analysis in clinical practice. MATERIALS AND METHODS: A total of 2,163 patients were screened for cancer susceptibility, using a solution-based capture method. A panel of 52 genes was used for targeted NGS. The capture-based approach enables computational analysis of CNVs from NGS data. We studied the performance of the CNV module of the commercial software suite SeqPilot (JSI Medical Systems) and of the non-commercial tool panelcn.MOPS. Additionally, we tested the performance of digital multiplex ligation-dependent probe amplification (digitalMLPA). RESULTS: Pathogenic/likely pathogenic variants (P/LP) were identified in 464 samples (21.5%). CNV accounts for 10.8% (50/464) of pathogenic variants, referring to deletion/duplication of one or more exons of a gene. In patients with breast and ovarian cancer, CNVs accounted for 10.2% and 6.8% of pathogenic variants, respectively. In colorectal cancer patients, CNV accounted for 28.6% of pathogenic/likely pathogenic variants. CONCLUSION: In silico CNV detection tools provide a viable and cost-effective method to identify CNVs from NGS experiments. CNVs constitute a substantial percentage of P/LP variants, since they represent up to one of every ten P/LP findings identified by NGS multigene analysis; therefore, their evaluation is highly recommended to improve the diagnostic yield of hereditary cancer analysis.

Human papillomavirus in head and neck cancers: biology, prognosis, hope of treatment, and vaccines.

Human papillomaviruses (HPVs), especially type 16, are implicated in the development of a subset of head and neck squamous cell cancers (HNSCCs). This subset of oropharyngeal cancers possesses distinct clinical and laboratory features and outcome, and is particularly common in individuals who lack the traditional risk factors of tobacco and alcohol abuse. Moreover, the annual incidence of HPV-related HNSCCs has increased in the USA and Europe in the last few years. As HPV-associated HNSCCs share a better prognosis compared with stage-matched HPV-negative ones, selected patients could be spared the intensive and toxic treatment and be oriented to organ preservation strategies. Preventive HPV vaccines have already been designed against cervical cancer, and a further understanding of HPV-associated carcinogenesis could potentially lead to the development of HPV-targeted therapeutic strategies. This study summarizes the current knowledge regarding the epidemiology, biology, malignant transformation mechanisms, and prognosis of HPV-associated HNSCCs, and underlines the clinical implications of related treatments and prophylactic strategies.

Clinical Utility of Functional RNA Analysis for the Reclassification of Splicing Gene Variants in Hereditary Cancer.

BACKGROUND: Classification of splicing variants (SVs) in genes associated with hereditary cancer is often challenging. The aim of this study was to investigate the occurrence of SVs in hereditary cancer genes and the clinical utility of RNA analysis. MATERIAL AND METHODS: 1518 individuals were tested for cancer predisposition, using a Next Generation Sequencing (NGS) panel of 36 genes. Splicing variant analysis was performed using RT-PCR and Sanger Sequencing. RESULTS: In total, 34 different SVs were identified, 53% of which were classified as pathogenic or likely pathogenic. The remaining 16 variants were initially classified as Variant of Uncertain Significance (VUS). RNA analysis was performed for 3 novel variants. CONCLUSION: The RNA analysis assisted in the reclassification of 20% of splicing variants from VUS to pathogenic. RNA analysis is essential in the case of uncharacterized splicing variants, for proper classification and personalized management of these patients.

Responses to SARS-CoV-2 Vaccination in Patients with Cancer (ReCOVer Study): A Prospective Cohort Study of the Hellenic Cooperative Oncology Group.

Data on the effectiveness and safety of approved SARS-CoV-2 vaccines in cancer patients are limited. This observational, prospective cohort study investigated the humoral immune response to SARS-CoV-2 vaccination in 232 cancer patients from 12 HeCOG-affiliated oncology departments compared to 100 healthcare volunteers without known active cancer. The seropositivity rate was measured 2-4 weeks after two vaccine doses, by evaluating neutralising antibodies against the SARS-CoV-2 spike protein using a commercially available immunoassay. Seropositivity was defined as ≥33.8 Binding-Antibody-Units (BAU)/mL. A total of 189 patients and 99 controls were eligible for this analysis. Among patients, 171 (90.5%) were seropositive after two vaccine doses, compared to 98% of controls (p = 0.015). Most seronegative patients were males (66.7%), >70-years-old (55.5%), with comorbidities (61.1%), and on active treatment (88.9%). The median antibody titers among patients were significantly lower than those of the controls (523 vs. 2050 BAU/mL; p < 0.001). The rate of protective titers was 54.5% in patients vs. 97% in controls (p < 0.001). Seropositivity rates and IgG titers in controls did not differ for any studied factor. In cancer patients, higher antibody titers were observed in never-smokers (p = 0.006), women (p = 0.022), <50-year-olds (p = 0.004), PS 0 (p = 0.029), and in breast or ovarian vs. other cancers. Adverse events were comparable to registration trials. In this cohort study, although the seropositivity rate after two vaccine doses in cancer patients seemed satisfactory, their antibody titers were significantly lower than in controls. Monitoring of responses and further elucidation of the clinical factors that affect immunity could guide adaptations of vaccine strategies for vulnerable subgroups.

Real-world clinical outcome and toxicity data and economic aspects in patients with advanced breast cancer treated with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors combined with endocrine therapy: the experience of the Hellenic Cooperative Oncology Group.

BACKGROUND: We evaluated real-world clinical outcomes and toxicity data and assessed treatment-related costs in patients with advanced breast cancer who received treatment with cyclin-dependent kinase inhibitors (CDKi). PATIENTS AND METHODS: We conducted a prospective-retrospective analysis of patients with advanced hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer who received a CDKi, in combination with endocrine therapy, at any line of treatment. The primary endpoint was progression-free survival (PFS). Cost analysis was conducted from a public third-payer (National Organization for Healthcare Services Provision (EOPYY)) perspective, assessing only costs related to direct medical care, including drug therapy costs and adverse drug reaction (ADR)-related costs. RESULTS: From July 2015 to October 2019, 365 women received endocrine therapy combined with CDKi; median age was 61 years, postmenopausal 290 (80.6%) patients. CDKi were administered as first-line treatment in 149 (40.9%) patients, second-line treatment in 96 (26.4%) and third-line treatment and beyond in 119 (32.7%) patients. The most common adverse events were neutropenia, anaemia, thrombocytopenia and fatigue. Grade 3-4 adverse events occurred in 86 (23.6%) patients, whereas 8 (2.2%) patients permanently discontinued treatment due to toxicity. The median PFS for patients who received CDKi as first-line, second-line and third-line treatment and beyond was 18.7, 12 and 7.4 months, respectively. The median overall survival since the initiation of CDKi treatment was 29.9 months (95% CI: 23.0-not yet reached (NR)). The mean pharmaceutical therapy cost estimated per cycle was 2 724.12 € for each patient, whereas the main driver of the ADR-related costs was haematological adverse events. CONCLUSIONS: Treatment with CDKi was well tolerated, with a low drug discontinuation rate. Patients who received CDKi as first-line treatment had improved PFS and OS compared with second-line treatment and beyond. The main component of direct medical costs assessed in the cost analysis comprises CDKi pharmaceutical therapy costs. TRIAL REGISTRATION NUMBER: NCT04133207.

Combination chemotherapy with docetaxel, vinorelbine and estramustine phosphate in metastatic androgen-resistant prostate cancer: a single institution experience.

UNLABELLED: The aim of this study was to evaluate the activity and toxicity of docetaxel, vinorelbine and oral estramustine in androgen-resistant prostate cancer (ARPC). PATIENTS AND METHODS: Fifty-two eligible patients were treated with docetaxel at 30 mg/m2 (day 1 and 8), vinorelbine at 20 mg/m2 (day 1 and 8), and oral estramustine of 280 mg p.o. (daily on days 1 to 7) every 3 weeks for 12 cycles. Patients with osseous metastases received zoledronic acid of 4 mg every 3 weeks. Low molecular weight heparin was administered on a prophylaxis basis to all patients. RESULTS: A prostate-specific antigen (PSA) response > or = 50% from baseline was obtained in 29 (56%; 95% confidence interval [CI], 42-70%) patients. Objective responses among the 25 patients with measurable disease were observed in 48% (95% CI, 27-69%), including 1 patient with complete response (CR) and 11 patients with partial response (PR). Patients with extraosseous only, skeletal only, and extraosseous and skeletal metastases showed different PSA responses (87% vs. 44% vs. 59%, respectively, p = 0.094). Furthermore, patients with soft tissue disease only showed insignificantly better PSA response than those with skeletal metastases (response rate: 87% vs. 50%, p = 0.064). The median progression-free survival was 7.6 months (95% CI, 6.7-8.4 months) and the median overall survival was 18.2 months (95% CI, 15.5-20.8 months). The only parameters which were found to have an impact on survival were the extent of disease and the baseline levels of PSA. Toxicity was generally mild except for myelotoxicity. Neutropenia grade 3/4 was recorded in 33% of patients and 6% experienced febrile neutropenia. Anemia and thrombocytopenia grade 3 or 4 were not a problem. Three patients (6%) developed grade 3 sensory neuropathy and 2 patients (4%) developed grade 3 fatigue. Edema grade 3 occurred in 1 (2%) patient and thromboembolism grade 3 occurred in 2 (4%) patients. CONCLUSION: The combination of docetaxel, vinorelbine and oral estramustine is a well-tolerated regimen with high biochemical and objective response rates in patients with ARPC.

A pleomorphic rhabdomyosarcoma mimicking an inguinal hernia: a case report and review of the literature.

A 59-year-old male presented with a painful right inguinal swelling and deep vein thrombosis at the ipsilateral leg. An inguinal hernia was initially diagnosed, but during surgery a large mass was found anteriorly to the peritoneal sheaths. Histology revealed a high-grade pleomorphic rhabdomyosarcoma. The mass advanced rapidly, occupying the whole right iliac fossa and metastasizing to the lung. Despite first- and second-line chemotherapy, the patient deteriorated rapidly and died. Rhabdomyosarcomas should be managed in specialized centres as they have prognostic factors and histologic features still controversial and poorly clarified.