New Frontiers in Treatment for Gynecologic Cancers

The most frequently diagnosed histological types of cervical cancer (CC) are squamous cell carcinoma (SCC) and adenocarcinoma (ADC). Clinically, the prognosis of both types is controversial. A molecular profile that distinguishes each histological subtype and predicts the prognosis would be of great benefit to CC patients. Methods: The transcriptome of CC patients from The Cancer Genome Atlas (TCGA) was analyzed using the DESeq2 package to obtain the differentially expressed genes (DEGs) between ADC and SCC. The DEGs were validated on a publicly available Mexican-Mestizo patient transcriptome dataset (GSE56303). The global biological pathways involving the DEGs were obtained using the Webgestalt platform. The associations of the DEGs with Overall Survival (OS) were assessed. Finally, three DEGs were validated by RT-qPCR in an independent cohort of Mexican patients. Results. The molecular profiles of ADC and SCC of the CC patients of the TCGA database and the Mexican-Mestizo cohort (GSE56303) were determined obtaining 1768 and 88 DEGs, respectively. Strikingly, 70 genes were concordant—with similar Log2FoldChange values—in both cohorts. The 70 DEGs were involved in IL-17, JAK/STAT, and Ras signaling. Kaplan-Meier OS analysis from the Mexican-Mestizo cohort showed that higher GABRB2 and TSPAN8 and lower TMEM40 expression were associated with better OS. Similar results were found in an independent Mexican cohort. Conclusions: Molecular differences were detected between the ADC and SCC subtypes; however, further studies are required to define the appropriate prognostic biomarker for each histological type. Full article

Minimally invasive surgery (MIS) is performed to treat cervical cancer patients; however, a recent study showed that MIS was associated with higher recurrence and death rate compared with abdominal radical hysterectomy (ARH). In the current study, the prognosis of patients with early-stage cervical cancer who underwent MIS with vaginal closure or ARH was evaluated. One hundred and eighty-two patients underwent radical hysterectomy for cervical cancer with stage of IA2, IB1, and IIA1. MIS was performed by laparoscopy or a robot using the vaginal closure method. Disease-free survival (DFS) and overall survival (OS) were evaluated between the groups. Among the patients, 67 underwent MIS and 115 underwent ARH. The recurrence rate was 4.5% in MIS patients and 3.5% in ARH patients with a median follow-up (interquartile range) of 36 (18–60) and 78 (48–102) months, respectively. DFS and OS were not different between the groups (3y-DFS, 95.3% vs. 96.1%, p = 0.6; 3y-OS, 100% vs. 100%, p = 0.06). In early-stage cervical cancer patients, MIS with vaginal closure did not increase the risk for recurrence or death. Surgical techniques and procedures to avoid spillage of tumor cells could be important for a better prognosis. Full article

Ovarian cancer (OC) is the leading cause of death among women with gynecologic malignancy. Breast Cancer Susceptibility Gene 1 (BRCA 1) and Breast Cancer Susceptibility Gene 2 (BRCA 2) germline mutations confer an estimated 20 to 40 times increased risk of OC when compared to the general population. The majority of BRCA-associated OC is identified in the late stage, and no effective screening method has been proven to reduce mortality. Several pharmacologic and surgical options exist for risk-reduction of gynecologic malignancy in BRCA 1/2 mutation carriers. This review summarizes up-to-date research on pharmacologic risk-reducing interventions, including the oral contraceptive pill, acetylsalicylic acid/nonsteroidal anti inflammatory drugs (ASA/NSAID) therapy, and denosumab, and surgical risk-reducing interventions, including risk-reducing bilateral salpingo-oophorectomy, salpingectomy with delayed oophorectomy, and hysterectomy at the time of risk-reducing bilateral salpingo-oophorectomy. Full article

Individuals with proven hereditary cancer syndrome (HCS) such as BRCA1 and BRCA2 have elevated rates of ovarian, breast, and other cancers. If these high-risk people can be identified before a cancer is diagnosed, risk-reducing interventions are highly effective and can be lifesaving. Despite this evidence, the vast majority of Canadians with HCS are unaware of their risk. In response to this unmet opportunity for prevention, the British Columbia Gynecologic Cancer Initiative convened a research summit “Gynecologic Cancer Prevention: Thinking Big, Thinking Differently” in Vancouver, Canada on 26 November 2021. The aim of the conference was to explore how hereditary cancer prevention via population-based genetic testing could decrease morbidity and mortality from gynecologic cancer. The summit invited local, national, and international experts to (1) discuss how genetic testing could be more broadly implemented in a Canadian system, (2) identify key research priorities in this topic and (3) outline the core essential elements required for such a program to be successful. This report summarizes the findings from this research summit, describes the current state of hereditary genetic programs in Canada, and outlines incremental steps that can be taken to improve prevention for high-risk Canadians now while developing an organized population-based hereditary cancer strategy. Full article

Primary vaginal cancer is a rare gynecologic malignancy. Given the rarity of the disease, standardized approaches to management are limited, and a great variety of therapeutic conditions are endorsed. This paper reviews advances in surgical approaches, radiation, chemoradiation, and immunotherapy. Advances in surgical management including the increasing use of laparoscopic and endoscopic approaches, as well as the novel techniques in vaginal reconstruction, are reviewed. Concurrent chemoradiation remains a mainstay of treatment for vaginal cancer and has improved local control of disease and overall survival. Additionally, with metastatic disease or situations where toxicity from CCRT is unacceptable, systemic therapies including immunotherapy approaches are reviewed. Full article

This review of the meaningful data from 2021 on cervical, endometrial, and ovarian cancers aims to provide an update of the most clinically relevant studies presented at important oncologic congresses during the year (the American Society of Clinical Oncology (ASCO) Annual Meeting, the European Society for Medical Oncology (ESMO) Congress and the Society of Gynecologic Oncology (SGO) Annual Meeting). Despite the underlying existence of the COVID-19 pandemic, the last year has been notable in terms of research, with significant and promising advances in gynecological malignancies. Several major studies reporting the effects of innovative therapies for patients with cervical, endometrial, and ovarian cancers might change the medical practice in the future. Full article

Sentinel lymph node (SLN) mapping is becoming an acceptable alternative to full lymphadenectomy for evaluating lymphatic spread in clinical stage I endometrial cancer (EC). While the assessment of pelvic and para-aortic lymph nodes is part of the surgical staging of EC, there is a long-standing debate over the therapeutic value of full lymphadenectomy in this setting. Although lymphadenectomy offers critical information on lymphatic spread and prognosis, most patients will not derive oncologic benefit from this procedure as the majority of patients do not have lymph node involvement. SLN mapping offers prognostic information while simultaneously avoiding the morbidity associated with an extensive and often unnecessary lymphadenectomy. A key factor in the decision making when planning for EC surgery is the histologic subtype. Since the risk of lymphatic spread is less than 5% in low-grade EC, these patients might not benefit from lymph node assessment. Nonetheless, in high-grade EC, the risk for lymph node metastases is much higher (20–30%); therefore, it is crucial to determine the spread of disease both for determining prognosis and for tailoring the appropriate adjuvant treatment. Studies on the accuracy of SLN mapping in high-grade EC have shown a detection rate of over 90%. The available evidence supports adopting the SLN approach as an accurate method for surgical staging. However, there is a paucity of prospective data on the long-term oncologic outcome for patients undergoing SLN mapping in high-grade EC, and more trials are warranted to answer this question. Full article

Cervical cancer is the most common gynecologic malignancy and the fourth most common cancer in women worldwide. Over the last two decades, minimally invasive surgery (MIS) emerged as the mainstay in the surgical management of cervical cancer, bringing advantages such as lower operative morbidity and shorter hospital stay compared to open surgery while maintaining comparable oncologic outcomes in numerous retrospective studies. However, in 2018, a prospective phase III randomized controlled trial, “Laparoscopic Approach to Carcinoma of the Cervix (LACC)”, unexpectedly reported that MIS was associated with a statistically significant poorer overall survival and disease-free survival compared to open surgery in patients with early-stage cervical cancer. Various hypotheses have been raised by the authors to try to explain these results, but the LACC trial was not powered to answer those questions. In this study, through an exhaustive literature review, we wish to explore some of the potential causes that may explain the poorer oncologic outcomes associated with MIS, including the type of MIS surgery, the size of the lesion, the impact of CO₂ pneumoperitoneum, prior conization, the use of uterine manipulator, the use of protective measures, and the effect of surgical expertise/learning curve. Full article

Background: Over the past two decades, there has been significant advancement in the management of cervical cancer, particularly in the domain of definitive chemoradiotherapy for locally advanced cervical cancer (LACC). Indeed, radiation treatment paradigms have shifted from a two-dimensional (2D) approach solely based on anatomical bony landmarks, to an image-guided three-dimensional (3D) approach, with the goal of delivering doses more precisely to clinical targets with an increased sparing of organs-at-risk. Methods: This is a narrative review on the advances in radiation technologies for the treatment of cervical cancer. Using the PubMed database, we identified articles published in English up until November 18, 2021 on the treatment of LACC with external beam radiotherapy (EBRT) and brachytherapy. A search of the Clinicaltrials.gov and Clinicaltrialsregister.eu retrieved information on ongoing clinical trials on the topic of combined immunotherapy and radiotherapy in cervical cancer. Results: We highlight the historical evolution from the use of 2D radiotherapy to 3D-conformal radiotherapy, and then intensity modulated radiotherapy (IMRT) for the delivery of EBRT. We also discuss advances in brachytherapy, notably the transition to 3D image-guided adaptive brachytherapy (3D-IGABT). In this context, we highlight large cohort studies that were recently constructed and have shown significant improvement in local control and treatment-related toxicities with 3D-IGABT. Finally, we discuss other advances in the field, notably the use of stereotactic body radiotherapy (SBRT) as a substitute to brachytherapy, and the addition of immunotherapy to chemoradiation. Conclusions: The use of IG-IMRT and 3D-IGABT have considerably improved treatment outcomes and toxicity profiles for patients with LACC, and are now considered the gold standard in many countries. The use of SBRT boost as a replacement for brachytherapy has been associated with increased toxicity and decreased efficacy and should be used with caution in the context of clinical trials. New experimental approaches include the addition of immunotherapy to chemoradiation regimens. Full article

Endometrial carcinoma (EC) is traditionally treated with surgery and adjuvant treatment depending on clinicopathological risk factors. The genomic analysis of EC in 2013 and subsequent studies using immunohistochemistry have led to the current EC molecular classification into: polymerase epsilon mutated (POLEmut), p53 abnormal (p53abn), mismatch repair deficient (MMRd), and no specific molecular profile (NSMP). The four groups have prognostic value and represent a promising tool for clinical decision-making regarding adjuvant treatment. Molecular classification was integrated into the recent European Society of Gynecologic Oncology (ESGO) management guidelines. POLEmut EC has favorable outcomes and retrospective studies found that omitting adjuvant treatment is safe in this group; two prospective clinical trials, PORTEC-4 and TAPER, are ongoing to assess this. p53 abn is associated with increased recurrence, decreased survival, and benefitted from chemotherapy in the PORTEC-3 subgroup molecular analysis. The clinical trials PORTEC-4a and CANSTAMP will prospectively assess this. MMRd and NSMP groups have intermediate prognosis and will likely continue to rely closely on clinicopathological features for adjuvant treatment decisions. In addition, the molecular classification has led to exploring novel treatments such as checkpoint inhibitors. Overall, the molecular perspective on EC and associated clinical trials will likely refine EC risk stratification to optimize care and avoid overtreatment. Full article

Enhanced Recovery After Surgery (ERAS) is a global surgical quality improvement program that started in colorectal surgery and has now expanded to numerous specialties, including gynecologic oncology. ERAS guidelines comprise multidisciplinary, evidence-based recommendations in the preoperative, intraoperative, and postoperative period; these interventions broadly encompass patient education, anesthetic choice, multimodal pain control, avoidance of unnecessary drains, maintenance of nutrition, and prevention of emesis. Implementation of ERAS has been shown to be associated with improved clinical outcomes (length of hospital stay, complications, readmissions) and cost. Marx and colleagues first demonstrated the feasibility of ERAS in gynecologic oncology in 2003; since then, over 30 comparative studies and 4 guidelines have been published encompassing major gynecologic surgery, cytoreductive surgery, and vulvar/vaginal surgery. Implementation of ERAS in gynecologic oncology has been demonstrated to provide improvements in length of stay, complications, cost, opioid use, and patient satisfaction. Increased compliance with ERAS guidelines has been associated with greater improvement in outcomes. Full article

Prior to 1997, ovarian cancer (OC) was a ‘poor target’ for patient advocacy. At that time, there were only three OC researchers in Canada, little information available for women diagnosed, and no community of survivors existed. The Corinne Boyer Fund to advance OC was founded in 1997 (later renamed the National Ovarian Cancer Association (NOCA) and subsequently Ovarian Cancer Canada (OCC)), and a Blueprint for Action was established. NOCA developed training programs for public education, partnered with clinicians and scientists, established a Tissue Banking Network across Canada In 2015, the Ladyballs awareness campaign was launched nationally, giving the community a presence and voice. Strategic planning by the organization put advocacy for research funding as a top priority and, working with patients and researchers across the country, petitioned the government for C$10 million in research funding. In 2019, OCC received the funding. In 2020, the OvCAN project was launched with the aim to improve the outcomes of women diagnosed with OC. In the first three years of OvCAN, a pan-Canadian team of 25 Patient Partners was established, and 41 projects to date on research models, pre-clinical and clinical trials covering a wide spectrum of OC types have been funded. Full article