Purpose of Review
The treatment of patients with advanced gynecologic malignancies remains challenging. Advancements in genomics have led to recognition and development of individualized therapeutic ...targets. This article reviews the current trends in precision medicine for treatment of gynecologic cancers.
Recent Findings
With the identification of the molecular aberrations inherent to gynecologic malignancies, we have discovered targetable mutations. Specific to ovarian, endometrial and cervical cancers, potential therapeutic targets that have been identified and shown to have benefit include: hormonal therapies, anti-angiogenic agents, poly-ADP-ribose polymerase inhibitors (PARPi), and immunotherapy.
Summary
The adoption of targeted therapeutics for the treatment of gynecologic cancers has been gradual, but we have started to see the rapid employment of novel targeted agents into clinical trial development, leading to new treatment approvals. However, there are challenges to the universal precision medicine implementation, and future studies need to identify, discover, and validate robust biomarkers with strong prognostic/predictive capabilities.
The treatment for high risk or recurrent gestational trophoblastic neoplasia (GTN) is a highly toxic multi-agent chemotherapy. For patients with progressive or recurrent GTN, checkpoint inhibitors ...have demonstrated anti-tumor activity; however, identification of novel therapies for GTN remain an unmet need. Therefore, we sought to characterize the molecular landscape of GTN to identify potential therapeutic targets.
GTN samples were analyzed using a combination of molecular – next-generation sequencing (NGS) or whole exome sequencing (WES)- and protein- Immunohistochemistry (IHC) analyses. GTN samples encompassed complete moles, choriocarcinoma, epithelioid trophoblastic tumors (ETT), and placental site trophoblastic tumors (PSTT).
We analyzed 30 cases of GTN including 15 choriocarcinoma, 7 ETT, 5 PSTT, 1 invasive mole and 2 mixed histologies. The median age was 41.5. GTN samples were found to be PD-L1 positive (92.3%), tumor mutational burden (TMB) low (92.8%), and microsatellite stable (MSS) (100%). Forty-six percent of choriocarcinoma specimens contained a genomic alteration including TP53 (33%) and homologous recombination repair (HRR) (13%) genes. Alterations in RTK-RAS pathway signaling was present in 40% of ETT cases.
The high rate of PD-L1 positivity in this real-world database and reported in prior literature support continued clinical trial development evaluating immunotherapy for treatment of GTN. Other potential targeted treatments identified include Wee1, PARP and MEK inhibitors based on molecular alterations in TP53, HRR genes, and RTK-RAS pathways respectively.
•Treatment for recurrent GTN often requires multi-agent chemotherapy with high levels of toxicity.•Understanding the molecular profile of GTN may help identify less toxic, targeted therapies.•GTN samples express PD-L1 > 90% of the time.•ETT samples had alterations in the RTK-RAS pathway >40% of the time.
Our aim was to investigate the prevalence and potential risk factors for persistent and troublesome physical and psychological symptoms following treatment for ovarian cancer (OC).
OvQuest is an ...international, internet-based, cross-sectional questionnaire which explored symptom burden and quality of life (QOL) after treatment for OC. Eligible women were aged 18 and over, diagnosed with OC at least 6 months previously and had received chemotherapy. Self-report data were collected including demographics, diagnosis and treatment, and standardised instruments for treatment-related toxicities, QOL, physical activity (PA) and supportive care needs.
The survey included 1360 patients, of whom 421 (31%) had been treated for recurrent OC. 78% reported symptoms of peripheral neuropathy, 60% significant fatigue, 48% mood disturbance and 59% moderate-severe insomnia. Rates of fatigue, mood disorders, neuropathy and insomnia did not differ between women with or without recurrence. The majority of respondents were overweight or obese (high BMI, 59%) and 35% reported low PA. Low PA and high BMI were associated with poorer QOL scores and higher symptom burden across a range of domains.
Women living after a diagnosis of OC report a substantial and ongoing symptom burden which impacts significantly on their quality of life across multiple domains. The reported associations between obesity, physical inactivity and poor QOL warrant prospective evaluation of lifestyle interventions to improve QOL.
•There are a growing number of long term ovarian cancer survivors for whom quality of life is an important issue.•The health related quality of life of the study cohort was inferior to general population norms.•A strong association has been seen between obesity, physical inactivity and quality of life.•Recurrent disease status did not appear to be a significant contributor to symptom burden.
Although the association between high surgical volume and improved outcomes from procedures is well described, the mechanisms that underlie this association are uncertain. There is growing ...recognition that high-volume hospitals may not necessarily have lower complication rates but rather may be better at rescuing patients with complications. We examined the role of complications, failure to rescue from complications, and mortality based on hospital volume for ovarian cancer.
The Nationwide Inpatient Sample was used to identify women who underwent surgery for ovarian cancer from 1988 to 2009. Hospitals were ranked on the basis of their procedure volume. We determined the risk-adjusted mortality, major complication rate, and "failure to rescue" rate (mortality in patients with a major complication) for each tertile. Univariate and multivariate associations were then compared.
We identified 36,624 patients. The mortality rate for the cohort was 1.6%. The major complication rate was 20.4% at low-volume, 23.4% at intermediate-volume, and 24.6% at high-volume hospitals (P < .001). However, the rate of failure to rescue (death after a complication) was markedly higher at low-volume (8.0%) compared with high-volume hospitals (4.9%; P < .001). After accounting for patient and hospital characteristics, women treated at low-volume hospitals who experienced a complication were 48% more likely (odds ratio OR, 1.48; 95% CI, 1.11 to 1.99) to die than patients with a complication at a high-volume hospital.
Mortality is lower for patients with ovarian cancer treated at high-volume hospitals. The reduction in mortality does not appear to be the result of lower complications rates but rather a result of the ability of high-volume hospitals to rescue patients with complications.
OBJECTIVE:To estimate the influence of surgical volume on outcome and resource utilization for laparoscopic hysterectomy for benign indications.
METHODS:Patients who underwent laparoscopic ...hysterectomy from 2000 to 2010 and recorded in a commercial database were analyzed. Patients were stratified into tertiles according to the number of procedures performed by their surgeons and at their hospital. The influence of surgeon and hospital volume on perioperative morbidity and resource utilization was examined using multivariable regression models.
RESULTS:A total of 124,615 patients were identified. The overall complication rate decreased from 6.2% for low-volume surgeons to 4.2% for high-volume surgeons (P<.001). Patients operated on by high-volume surgeons were 25% (risk ratios RRs 0.75, 95% confidence interval CI 0.68–0.82) less likely to experience a complication. In multivariable models intraoperative complications, surgical-site complications, medical complications, prolonged hospitalization, and transfusion rates were lower for high-volume surgeons. Overall morbidity was 5.8% for women treated at low-volume hospitals compared with 4.7% at high-volume centers (P<.001). Women treated at high-volume centers were 18% (RR 0.82, 95% CI 0.75–0.90) less likely to experience a complication. Procedure costs for high-volume surgeons were $867 lower than for low-volume surgeons, and treatment at a high-volume center reduced costs by $966 per procedure.
CONCLUSION:Performance of laparoscopic hysterectomy by high-volume surgeons and at high-volume hospitals is associated with modest reductions in morbidity and lower costs.
LEVEL OF EVIDENCE:II
Abstract Ovarian cancer is a heterogeneous, rapidly progressive, highly lethal disease of low prevalence. The etiology remains poorly understood. Numerous risk factors have been identified, the most ...prominent involving an inherited predisposition in 10% of cases. Women with germline mutations associated with Hereditary Breast/Ovarian Cancer and Lynch syndromes have dramatically elevated risks (up to 46% and 12%, respectively). Risk-reducing salpingo-oophorectomy is the best method to prevent ovarian cancer in these high-risk women. Significant risk reduction is also seen in the general population who use oral contraceptives. Since up to 89% patients with early-stage disease have symptoms prior to diagnosis, increased awareness of the medical community may facilitate further workup in patients who otherwise would have had a delay. Despite enormous effort, there is no proof that routine screening for ovarian cancer in either the high-risk or general populations with serum markers, sonograms, or pelvic examinations decreases mortality. Further evaluation is needed to determine whether any novel biomarkers, or panels of markers, have clinical utility in early detection. Prospective clinical trials have to be designed and completed prior to offering of any of these new diagnostic tests. CA125 is currently the only biomarker recommended for monitoring of therapy as well as detection of recurrence. This commentary provides an overview on the background, screening and surveillance of ovarian cancer.
Low grade serous ovarian cancer (LGSOC) differs from high grade serous in terms of pathogenesis, molecular, genetic, and clinical features. Molecular studies have been hampered by small sample sizes, ...heterogenous histology, and lack of comprehensive testing. We sought to molecularly profile LGSOC in a homogenously tested, histologically confirmed cohort.
Using hot-spot and whole exome next generation sequencing (NGS), fusion gene analysis interrogating RNA, fragment analysis, in situ hybridization and/or immunohistochemistry, 179 specimens were evaluated by Caris Life Sciences (Phoenix, AZ). A second independent histologic review confirmed histology in 153 specimens.
Most frequently mutated genes (5% or greater) were members of the mitogen-activated protein kinase (MAPK) pathway: KRAS (23.7%, n = 36), NRAS (11.2%, n = 19), NF1 (7.9%, n = 5), and BRAF (6.6%, n = 10). Class III mutations were seen in 3 of 10 BRAF mutations while 7 were Class I V600E. Overall, estrogen and progesterone receptor expression was 80.2% (n = 130) and 27.8% (n = 45), respectively. Of those that were hormone negative, nearly 50% contained KRAS or NF1 mutations. None were NRAS mutated. Markers of response to immunotherapy were low to absent.
BRAF mutations were seen to be lower than those traditionally reported. With increased MAPK activation resulting in ligand independent activation of ERα, a role of combination therapy with hormonal and targeted therapy should be considered as 49.2% of hormone negative specimens were KRAS or NF1 mutated. Absence of immunotherapy biomarkers suggest limited benefit to immunotherapeutic agents.
•Low grade serous ovarian cancer has a unique mutational profile relative to high grade and borderline serous ovarian cancers.•BRAF mutations are rare (6.6%) and nearly a third were RAS dependent (a.k.a Class III)•Estrogen receptor expression is seen in 80% and commonly co-exist with NRAS and BRAF mutations.•Clinical biomarkers associated with response to immune checkpoint inhibitors are largely absent.
Ovarian cancer is increasingly recognized as a chronic disease whose treatment is often characterized by administration of multiple, sequential active agents, each of which may or may not be ...accompanied by a tumor response. Despite the large proportion of patients who relapse and undergo longer-term treatment, the question of optimal treatment duration has not been fully addressed to date. For patients who progress on therapy, the answer is straightforward: they are switched to another active agent, presumably having a different mechanism of action from previous therapies with, ideally, limited overlapping toxicities. However, for patients who remain in partial response or who have stable disease, the answer is less apparent and less clear. The majority of oncologists believe that treatment beyond 6 cycles of a given therapy does not provide any additional benefit to patients. There are some data to support that treatment strategy. However, with the advent of new, less toxic agents, treatment to progression should be further explored. Agents that are potentially well suited for extended treatment intervals may include such properties as absence of cumulative toxicity, non-cross-resistance, positive benefit on quality of life, and convenient schedule. A number of active agents in ovarian cancer (platinum, paclitaxel, topotecan, liposomal doxorubicin, docetaxel, gemcitabine, and etoposide) will be reviewed in the context of what is known about cumulative toxicity, potential adverse effects on patients' quality of life, and evidence addressing the potential benefits of longer-term treatment.
Abstract Objectives We performed a population-based analysis to determine the effect of histology on survival for women with invasive cervical cancer. Methods The Surveillance, Epidemiology and End ...Results database was used to identify women with stage IB-IVB cervical cancer treated from 1988 to 2005. Patients were stratified by histology (squamous, adenocarcinoma, and adenosquamous). Clinical characteristics, patterns of care, and outcomes were analyzed using multivariable logistic regression and Cox proportional hazards models. Results A total of 24,562 patients were identified including 18,979 (77%) women with squamous cell carcinomas, 4103 (17%) with adencarcinomas, and 1480 (6%) with adenosquamous tumors. Women with adenocarcinomas were younger, more often white, and more frequently married than patients with squamous cell tumors (p < 0.0001 for all). Patients with adenocarcinomas were more likely to present with early-stage disease (p < 0.0001). At diagnosis, 26.7% of women with adenocarcinomas had stage IB1 tumors compared to 16.9% of those with squamous cell carcinomas. Among women with early-stage (IB1-IIA) tumors, patients with adenocarcinomas were 39% (HR = 1.39; 95% CI, 1.23–1.56) more likely to die from their tumors than those with squamous cell carcinomas. For patients with advanced-stage disease (stage IIB-IVA) women with adenocarcinomas were 21% (HR = 1.21; 95% CI, 1.10–1.32) more likely to die from their tumors than those with squamous neoplasms. Five-year survival for stage IIIB neoplasms five-year survival was 31.3% (95% CI, 29.2–33.3%) for squamous tumors vs. 20.3% (95% CI, 14.2–27.1%) for adenocarcinomas. Conclusion Cervical adenocarcinomas are more common in younger women and white patients. Adenocarcinoma histology negatively impacts survival for both early and advanced-stage carcinomas.
•GTN has a known propensity to spread to the lungs and can cause serious pulmonary complications.•Chemotherapy can also lead to lung toxicity, placing GTN patients at uniquely high risk of serious ...pulmonary events.•Prompt management is crucial to optimize patient well-being and continuation of life-saving chemotherapy in these cases.•However, there is minimal published guidance on the management of these complications.•We identified strategies such as escalating care, inpatient chemotherapy, and conservative measures that aided management.
Gestational trophoblastic neoplasia (GTN) consists of rare malignancies of the placenta with a known propensity to metastasize to the lungs. GTN is treated with chemotherapeutic agents known to cause lung injury, further placing patients at risk for serious pulmonary events. In the literature, only a few reports of these complications and their management have been described. Here, we present two cases of GTN with pulmonary complications in the hopes of providing guidance in management. Management of these acute complications had to be balanced between continuation of life-saving therapy to reduce disease burden versus further exacerbation existing pulmonary disease.A review of the English language literature on pulmonary complications in GTN and chemotherapy was performed.
In these two cases, we identified key steps that were critical in management: inpatient chemotherapy, early intervention and transfer to an intensive unit when needed, multidisciplinary teams, and altering regimens to reduce lung toxicity. Sequelae of pulmonary injury secondary to chemotherapy can be similar to those secondary to metastases. Because consistent criteria for chemotherapy-induced lung injury has not been established, the true incidence of lung injury that is directly related to chemotherapy versus metastatic disease cannot always be parsed out, making management of these complications difficult. There is also a lack of centralized care for a rare disease like GTN and regional differences in incidence, which can lead to inconsistent treatment decisions. It therefore remains important to illuminate rarely seen complications and their management in the hopes of providing guidance to future clinicians.
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