Methylation patterns in serum DNA for early identification of disseminated breast cancer

BACKGROUND: Monitoring treatment and early detection of fatal breast cancer (BC) remains a major unmet need. Aberrant circulating DNA methylation (DNAme) patterns are likely to provide a highly specific cancer signal. We hypothesized that cell-free DNAme markers could indicate disseminated breast cancer, even in the presence of substantial quantities of background DNA. METHODS: We used reduced representation bisulfite sequencing (RRBS) of 31 tissues and established serum assays based on ultra-high coverage bisulfite sequencing in two independent prospective serum sets (n = 110). The clinical use of one specific region, EFC#93, was validated in 419 patients (in both pre- and post-adjuvant chemotherapy samples) from SUCCESS (Simultaneous Study of Gemcitabine-Docetaxel Combination adjuvant treatment, as well as Extended Bisphosphonate and Surveillance-Trial) and 925 women (pre-diagnosis) from the UKCTOCS (UK Collaborative Trial of Ovarian Cancer Screening) population cohort, with overall survival and occurrence of incident breast cancer (which will or will not lead to death), respectively, as primary endpoints. RESULTS: A total of 18 BC specific DNAme patterns were discovered in tissue, of which the top six were further tested in serum. The best candidate, EFC#93, was validated for clinical use. EFC#93 was an independent poor prognostic marker in pre-chemotherapy samples (hazard ratio [HR] for death = 7.689) and superior to circulating tumor cells (CTCs) (HR for death = 5.681). More than 70% of patients with both CTCs and EFC#93 serum DNAme positivity in their pre-chemotherapy samples relapsed within five years. EFC#93-positive disseminated disease in post-chemotherapy samples seems to respond to anti-hormonal treatment. The presence of EFC#93 serum DNAme identified 42.9% and 25% of women who were diagnosed with a fatal BC within 3–6 and 6–12 months of sample donation, respectively, with a specificity of 88%. The sensitivity with respect to detecting fatal BC was ~ 4-fold higher compared to non-fatal BC. CONCLUSIONS: Detection of EFC#93 serum DNAme patterns offers a new tool for early diagnosis and management of disseminated breast cancers. Clinical trials are required to assess whether EFC#93-positive women in the absence of radiological detectable breast cancers will benefit from anti-hormonal treatment before the breast lesions become clinically apparent

DNA methylation markers for early detection of women's cancer: promise and challenges

Breast, ovarian and endometrial cancers cause significant morbidity and mortality. Despite the presence of existing screening, diagnostic and treatment modalities, they continue to pose considerable unsolved challenges. Overdiagnosis is a growing problem in breast cancer screening and neither screening nor early diagnosis of ovarian or endometrial cancer is currently possible. Moreover, treatment of the diversity of these cancers presenting in the clinic is not sufficiently personalized at present. Recent technological advances, including reduced representation bisulfite sequencing, methylation arrays, digital PCR, next-generation sequencing and advanced statistical data analysis, enable the analysis of methylation patterns in cell-free tumor DNA in serum/plasma. Ongoing work is bringing these methods together for the analysis of samples from large clinical trials, which have been collected well in advance of cancer diagnosis. These efforts pave the way for the development of a noninvasive method that would enable us to overcome existing challenges to personalized medicine

Clinical research in ovarian cancer: consensus recommendations from the Gynecologic Cancer InterGroup

The Gynecologic Cancer InterGroup (GCIG) sixth Ovarian Cancer Conference on Clinical Research was held virtually in October, 2021, following published consensus guidelines. The goal of the consensus meeting was to achieve harmonisation on the design elements of upcoming trials in ovarian cancer, to select important questions for future study, and to identify unmet needs. All 33 GCIG member groups participated in the development, refinement, and adoption of 20 statements within four topic groups on clinical research in ovarian cancer including first line treatment, recurrent disease, disease subgroups, and future trials. Unanimous consensus was obtained for 14 of 20 statements, with greater than 90% concordance in the remaining six statements. The high acceptance rate following active deliberation among the GCIG groups confirmed that a consensus process could be applied in a virtual setting. Together with detailed categorisation of unmet needs, these consensus statements will promote the harmonisation of international clinical research in ovarian cancer

Radiotherapy Versus Inguinofemoral Lymphadenectomy as Treatment for Vulvar Cancer Patients With Micrometastases in the Sentinel Node: Results of GROINSS-V II

PURPOSE: The Groningen International Study on Sentinel nodes in Vulvar cancer (GROINSS-V)-II investigated whether inguinofemoral radiotherapy is a safe alternative to inguinofemoral lymphadenectomy (IFL) in vulvar cancer patients with a metastatic sentinel node (SN). METHODS: GROINSS-V-II was a prospective multicenter phase-II single-arm treatment trial, including patients with early-stage vulvar cancer (diameter < 4 cm) without signs of lymph node involvement at imaging, who had primary surgical treatment (local excision with SN biopsy). Where the SN was involved (metastasis of any size), inguinofemoral radiotherapy was given (50 Gy). The primary end point was isolated groin recurrence rate at 24 months. Stopping rules were defined for the occurrence of groin recurrences. RESULTS: From December 2005 until October 2016, 1,535 eligible patients were registered. The SN showed metastasis in 322 (21.0%) patients. In June 2010, with 91 SN-positive patients included, the stopping rule was activated because the isolated groin recurrence rate in this group went above our predefined threshold. Among 10 patients with an isolated groin recurrence, nine had SN metastases > 2 mm and/or extracapsular spread. The protocol was amended so that those with SN macrometastases (> 2 mm) underwent standard of care (IFL), whereas patients with SN micrometastases (≤ 2 mm) continued to receive inguinofemoral radiotherapy. Among 160 patients with SN micrometastases, 126 received inguinofemoral radiotherapy, with an ipsilateral isolated groin recurrence rate at 2 years of 1.6%. Among 162 patients with SN macrometastases, the isolated groin recurrence rate at 2 years was 22% in those who underwent radiotherapy, and 6.9% in those who underwent IFL (P = .011). Treatment-related morbidity after radiotherapy was less frequent compared with IFL. CONCLUSION: Inguinofemoral radiotherapy is a safe alternative for IFL in patients with SN micrometastases, with minimal morbidity. For patients with SN macrometastasis, radiotherapy with a total dose of 50 Gy resulted in more isolated groin recurrences compared with IFL

State of the Art Review: Emerging Therapies: The Use of Insulin Sensitizers in the Treatment of Adolescents with Polycystic Ovary Syndrome (PCOS)

PCOS, a heterogeneous disorder characterized by cystic ovarian morphology, androgen excess, and/or irregular periods, emerges during or shortly after puberty. Peri- and post-pubertal obesity, insulin resistance and consequent hyperinsulinemia are highly prevalent co-morbidities of PCOS and promote an ongoing state of excess androgen. Given the relationship of insulin to androgen excess, reduction of insulin secretion and/or improvement of its action at target tissues offer the possibility of improving the physical stigmata of androgen excess by correction of the reproductive dysfunction and preventing metabolic derangements from becoming entrenched. While lifestyle changes that concentrate on behavioral, dietary and exercise regimens should be considered as first line therapy for weight reduction and normalization of insulin levels in adolescents with PCOS, several therapeutic options are available and in wide use, including oral contraceptives, metformin, thiazolidenediones and spironolactone. Overwhelmingly, the data on the safety and efficacy of these medications derive from the adult PCOS literature. Despite the paucity of randomized control trials to adequately evaluate these modalities in adolescents, their use, particularly that of metformin, has gained popularity in the pediatric endocrine community. In this article, we present an overview of the use of insulin sensitizing medications in PCOS and review both the adult and (where available) adolescent literature, focusing specifically on the use of metformin in both mono- and combination therapy

ESMO-ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease

The development of guidelines is one of the core activities of the European Society for Medical Oncology (ESMO) and European Society of Gynaecologial Oncology (ESGO), as part of the mission of both societies to improve the quality of care for patients with cancer across Europe. ESMO and ESGO jointly developed clinically relevant and evidence-based recommendations in several selected areas in order to improve the quality of care for women with ovarian cancer. The ESMO–ESGO consensus conference on ovarian cancer was held on April 12–14, 2018 in Milan, Italy, and comprised a multidisciplinary panel of 40 leading experts in the management of ovarian cancer. Before the conference, the expert panel worked on five clinically relevant questions regarding ovarian cancer relating to each of the following four areas: pathology and molecular biology, early-stage and borderline tumours, advanced stage disease and recurrent disease. Relevant scientific literature, as identified using a systematic search, was reviewed in advance. During the consensus conference, the panel developed recommendations for each specific question and a consensus was reached. The recommendations presented here are thus based on the best available evidence and expert agreement. This article presents the recommendations of this ESMO–ESGO consensus conference, together with a summary of evidence supporting each recommendation

Polycystic ovary syndrome

The document attached has been archived with permission from the editor of the Medical Journal of Australia. An external link to the publisher’s copy is included.Polycystic ovary syndrome (PCOS) affects 5-20% of women of reproductive age worldwide. The condition is characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology (PCOM) - with excessive androgen production by the ovaries being a key feature of PCOS. Metabolic dysfunction characterized by insulin resistance and compensatory hyperinsulinaemia is evident in the vast majority of affected individuals. PCOS increases the risk for type 2 diabetes mellitus, gestational diabetes and other pregnancy-related complications, venous thromboembolism, cerebrovascular and cardiovascular events and endometrial cancer. PCOS is a diagnosis of exclusion, based primarily on the presence of hyperandrogenism, ovulatory dysfunction and PCOM. Treatment should be tailored to the complaints and needs of the patient and involves targeting metabolic abnormalities through lifestyle changes, medication and potentially surgery for the prevention and management of excess weight, androgen suppression and/or blockade, endometrial protection, reproductive therapy and the detection and treatment of psychological features. This Primer summarizes the current state of knowledge regarding the epidemiology, mechanisms and pathophysiology, diagnosis, screening and prevention, management and future investigational directions of the disorder.Robert J Norman, Ruijin Wu and Marcin T Stankiewic