This article is part IV of a series. View parts I, II, and III:

Evolving Paradigms in Gynecologic Cancer> >

Novel antitumor agents are currently being evaluated in clinical trials for use in various gynecological cancers. The majority of new agents in late-phase trials are antiangiogenic drugs that inhibit the formation of new blood vessels in the tumor microenvironment by targeting growth factors, tyrosine kinase receptors, and other molecular targets. Other promising strategies include poly(ADP-ribose) polymerase (PARP) inhibitors that exploit deficient DNA repair pathways in cancerous cells and immunotherapies that enhance the ability of the patient&rsquo;s own immune system to target and eliminate malignant cells.

Angiogenesis is a key component of a tumor&rsquo;s microenvironment, and inhibiting pro-angiogenic signalling has been an effective strategy in treating a variety of solid tumors, including colon, lung, brain, and liver, among others. As antiangiogenic drugs have become approved for use in a greater number of different tumors, attention has turned to their potential for treating gynecologic cancers, and multiple abstracts have been presented at national and international meetings.

Members of the VEGF protein family are key components of pro-angiogenic signaling and also play an important role in maintaining healthy functioning in the ovaries. Therefore, it has been hypothesized that controlling excessive VEGF and abnormal angiogenesis is of particular importance in ovarian cancer.

This expectation has been borne out by results obtained with the anti-VEGF antibody bevacizumab, which has generated a number of positive trial results in gynecologic cancers. In addition to the recent approval by the FDA for use of bevacizumab in advanced ovarian and cervical cancers (see current therapies section), several other anti-VEGF agents are in late-stage trials.

FIGURE 2: Schematic of the components of the angiogenic pathway and antiangiogenic agents.

Other antiangiogenic agents with VEGF-independent mechanisms of action are also in late-stage trials for treatment of gynecologic cancers.

gives an overview of the various components of the angiogenic pathway in the cell and also depicts which steps of the cascade can be blocked with drugs.

Trebananib (AMG 386) is a peptide-antibody fusion protein that interferes with angiogenic signaling by binding to both angiopoietin-1 (Ang1) and angiopoietin-2 (Ang2) and preventing their interaction with the Tie2 receptor. Since the mechanism of trebananib is VEGF- independent, it has a different toxicity profile than anti-VEGF drugs, such as bevacizumab. The recently published results from the phase III TRINOVA-1 trial have shown that adding trebananib to paclitaxel chemotherapy in patients with recurrent EOC improved PFS while avoiding typical anti-VEGF adverse events.

As with bevacizumab, no improvement in OS has been shown with this agent.

Pazopanib is a tyrosine kinase inhibitor that blocks angiogenesis by targeting multiple tyrosine kinase receptors, including VEGFR-1, VEGFR-2, and VEGFR-3, as well as platelet-derived growth factor receptor and c-Kit. Results from a phase III trial investigating pazopanib as a maintenance therapy in patients with ovarian cancer after first-line therapy show that this drug is associated with increased PFS in these patients by a median of 5.6 months.

However, like other antiangiogenic agents, this trial found no effect on OS by pazopanib. Furthermore, post-hoc analysis of the trial data indicated that the increase in PFS was not observed in East Asian patients, suggesting that population stratification may be necessary to determine patient subgroups that experience the greatest benefit from pazopanib therapy.

Antiangiogenic therapy has shown potential in various gynecologic cancers, particularly cervical and ovarian; however, benefits such as OS have often been observed only in subsets of patient populations in trials. At the same time, trials have also reported significant toxicities, including diarrhea, nausea, fatigue, and hypertension.

Therefore, biomarkers to direct this type of treatment are likely to be key toward maximizing its potential.

The presence of malignant ascites is a potential clinical biomarker that has been associated with increased VEGF expression and is therefore hypothesized to be predictive of bevacizumab efficacy. Results released this year from the GOG 218 trial have indicated that patients with malignant ascites had poorer prognoses and derived greater benefit, including improved OS, from treatment with bevacizumab than those without them.

Other biomarkers have been proposed as indicators of response to antiangiogenic treatment. Decreased expression of the microRNA miR-378 and the resulting upregulation of its downstream target genes,

, were associated with improved PFS in patients treated with bevacizumab.

Conversely, low levels of Ang2 in circulating plasma have been associated with poor response to bevacizumab in pancreatic cancer.63 This association is thought to reflect the fact that antiangiogenic therapies are most effective in disease settings that are highly angiogenic.

FIGURE 3. Schematic of the role of PARP in the base excision DNA repair pathway.

An analysis of potential biomarkers has been included in various phase III trials of bevacizumab and produced promising candidates. Mutations of

receptors, tumor expression levels of neuropilin-1, and circulating levels of all 3 have been identified as strong biomarker candidates.

More research is required, however, as these biomarkers have been shown to be prognostic of outcome, but not predictive of response to antiangiogenic therapy.

The PARP1 enzyme is involved in the normal function of DNA repair pathways shown in

. By inhibiting the catalytic action of this protein, PARP inhibitors can cause PARP1 to be sequestered in complexes with damaged DNA, preventing damage repair and inducing double-stranded breaks.65 Although these agents were developed for use in cancers with defective homologous recombination function (eg,

- mutant tumors), recent data indicate that PARP inhibitors may have broader efficacy, including in combination with DNAdamaging agents in cancers with normal DNA repair function.

Development of PARP inhibitors for gynecologic cancers is most advanced in ovarian cancer, in which there is a high incidence of inherited or acquired

gene mutations, due to the demonstrated efficacy and specificity of PARP inhibitors for cancer cells with defective

A phase II study has shown responses to the PARP inhibitor olaparib (AZD2281) in patients with advanced, chemotherapy-resistant ovarian cancer,

and 2 phase III trials are ongoing to investigate the efficacy of olaparib in

In December, 2014, the FDA approved the use of olaparib in patients with advanced ovarian cancer who have

gene mutations and have progressed on at least 3 previous chemotherapies.

Another phase III trial is testing the PARP inhibitor niraparib (MK-4827) as maintenance therapy in platinum-sensitive ovarian cancer.70 Additionally, data presented at the 2014 Society of Gynecologic Oncology 45th Annual Meeting on Women&rsquo;s Cancer indicated that the PARP inhibitor veliparib (ABT-888) can produce responses even in patients with persistent or recurrent ovarian cancer,

providing patients with a possible alternative when other treatments have failed.

TABLE 3. Clinical Trials Investigating PARP Inhibitors in BRCA-Mutation-Negative Gynecologic Cancers

Olaparib in combination with carboplatin for refractory/recurrent gynecologic cancers

Veliparib in combination with topotecan in patients with relapsed epithelial ovarian cancer with negative or unknown BRCA status

Veliparib, topotecan, and filgrastim or pegfilgrastim in patients with persistent/recurrent cervical cancer

Veliparib with cisplatin and paclitaxel in patients with advanced, persistent, or recurrent cervical cancer

All clinical trials are found at www.clinicaltrials.gov and listed according to their NCT identifier.

Investigations using preclinical models have shown that cancers with decreased expression of phosphatase and tensin homolog (PTEN), including many endometrial cancers, are sensitive to PARP inhibitors.

Additionally, another preclinical study has shown that veliparib can potentiate the antitumor effects of DNA-damaging chemotherapy and radiation.

These results have led to growing interest in PARP inhibitors in

-mutation negative gynecologic malignancies such as endometrial and cervical cancers, although these efforts have not yet reached phase III trials. A partial list of these trials is shown in

Although interest in utilizing PARP inhibition clinically has primarily focused on patients with either germline or somatic BRCA mutations, several studies have identified other biomarkers that may predict responsiveness to PARP inhibition. Many of these candidates are also part of the cellular DNA-repair machinery, while others, such as PTEN, are not.

One such DNA-repair biomarker is the meiotic recombination 11 (MRE-11) gene. MRE-11 is part of the cellular mechanism that detects and repairs DNA double-strand breaks, and a recent paper reported that its protein is lost in over 30% of endometrial cancers.

Unsurprisingly, this group found that the absence of MRE-11 protein predicts sensitivity to PARP inhibition.

The micro-RNA miR-182 regulates the expression of BRCA1, and thus can affect the sensitivity of some cancers to PARP inhibition. Increased expression of miR-182 decreases expression of BRCA1, and therefore sensitizes cells to PARP inhibitors, while decreased miR-182 expression has the opposite effect.

Treatments that induce the patient&rsquo;s own immune system to target malignant cells (ie, immunotherapies) have become the subject of intense interest in many different tumor types in recent years. Although the development of immunotherapeutic agents for use in gynecologic cancers is less advanced than many antiangiogenic drugs, striking results have been reported in several early-stage trials, and rapid progress is expected in the near future.

Components of the immune checkpoint system are often aberrantly expressed by tumors or normal cells in the tumor microenvironment. In the healthy state, this system of receptors and ligands prevents immune T cells from attacking the body&rsquo;s own cells. However, malignant cells or antigen-presenting cells in the microenvironment can use the expression of checkpoint ligands to evade immune surveillance. Several drugs have been developed to prevent the immune checkpoint system from being activated, which in turn increases immune targeting of tumor cells (

Nivolumab (Opdivo) is an antibody targeting the programmed cell death-1 (PD-1) receptor and prevents interaction with its ligand (PD-L1). By inhibiting this immune checkpoint, nivolumab and similar agents facilitate the activation of T cells against cancer cells that would otherwise evade immune detection. Data from a phase II trial presented at the 2014 American Society of Clinical Oncology (ASCO) Annual Meeting showed that nivolumab was able to produce responses in patients with advanced or relapsed, platinum-resistant ovarian cancer.

Other checkpoint inhibitors currently under development for use in ovarian cancer include ipilimumab, an antibody targeting cytotoxic T-lymphocyte antigen 4 (CTLA4),

Adoptive T-cell therapy (ACT) is an immunotherapeutic strategy in which patients are treated with autologous tumor-infiltrating lymphocytes (TILs) that target proteins expressed specifically by cancer cells. This type of approach is particularly amenable to cancers that are induced by viral infections and therefore express exogenous viral proteins. A study presented at the 2014 ASCO Annual Meeting reported that ACT with TILs selected for reactivity to 2 HPV oncoproteins, E6 and E7, was successful in producing responses in patients with metastatic cervical cancer.

Though this was a small study, it has shown the feasibility of this approach in a disease with few treatment options.

A novel agent to target cancerous cells that express HPV proteins is ADXS11-001, an attenuated strain of Listeria monocytogenes that has been genetically modified to express HPV proteins. This agent acts as a vaccine in that the bacteria induce a specific T-cell response targeting malignant cells expressing HPV antigens. Final data from a phase II study demonstrated activity by ADXS11-001 against recurrent cervical cancer.

There is an effort to evaluate the anticancer effects of drugs that are FDA-approved for nononcology indications. This approach has the potential to quickly bring new therapies to the clinic in gynecologic cancers because the pharmacokinetic and safety profiles for these approved medications are already established, so preclinical and early-stage trials are largely unnecessary.

FIGURE 4. Ipilimumab and nivolumab and the interactions they inhibit between antigenpresenting cells, T cells, and tumor cells.

Metformin has been the main focus of drug repurposing research in gynecologic cancers.55 It is currently used in patients with diabetes and polycystic ovarian syndrome and has multiple metabolic effects at the cellular level. It is hypothesized that cancers are vulnerable to the activation of the AMP-activated protein kinase cascade by metformin, which results in decreased protein synthesis and proliferation, among other effects (

). There is a body of preclinical and clinical evidence that indicate that metformin has anticancer effects, and its use is associated with increased survival in uterine, ovarian, and cervical cancers.

Several abstracts at the Society of Gynecologic Oncology&rsquo;s 45th Annual Meeting on Women&rsquo;s Cancers explored the possibility of using metformin clinically. Among the results presented, one group reported that metformin treatment in obese patients was most effective at reducing endometrial cancer cell proliferation in tumors with high Ki-67 expression.

However, another study did not find that metformin reduced the risk of developing endometrial cancer in a population-based cohort.

Because the clinical data reported so far were obtained in patients who suffered from obesity and diabetes and the molecular mechanism mediating its anticancer effects remains uncertain, the utility of metformin for the prevention or treatment of gynecologic cancers in the general population continues to be investigated. At present, the phase II/III trial GOG 286B is evaluating whether or not the addition of metformin to paclitaxel-carboplatin chemotherapy in patients with advanced-stage or recurrent ovarian and endometrial cancer improves patient outcomes.

Future Directions for Clinical Investigation

Targeted therapies, including antiangiogenic drugs, PARP inhibitors, and immunotherapies, are the subjects of intense development at this time. An improved understanding of both VEGF-dependent and VEGF-independent pathways of angiogenesis, DNA repair pathways, and immune surveillance have raised expectations that these drugs will be able to improve patient survival while avoiding toxicities associated with chemotherapies and radiation therapies. There are, however, many questions that remain to be answered regarding these emerging treatments including: what are the optimal duration and sequencing of these treatments; are they most effective as monotherapy or when combined with chemotherapeutic drugs; and how should clinicians identify patient populations that are most likely to benefit from these agents.

Late-phase clinical trials clearly need to incorporate the most appropriate endpoints into their design to be informative; however, in the case of ovarian cancer, there has been significant debate regarding which endpoints are the most relevant and useful. Improvement in OS is generally considered the gold-standard endpoint for cancer studies; however, several unique factors in the setting of ovarian cancer have made it very challenging to adequately measure OS. Longer survival times overall make it more likely that patients will receive subsequent lines of therapy after the conclusion of a trial, and there is a high rate of treatment arm crossover during trials themselves. These factors both contribute to making accurate determination of OS difficult, lengthy, and costly.

These obstacles have led to the acceptance of PFS and other endpoints in trials, and the FDA approval of bevacizumab for recurrent ovarian cancer was based, in part, on the increased PFS observed in the AURELIA trial.

FIGURE 5. Metformin effects on cellular metabolism.

In early 2014, the Society of Gynecologic Oncology (SGO) issued guidance for the design of trials in ovarian cancer in consultation with the National Cancer Institute&rsquo;s Clinical Therapy Evaluation Program, the FDA, representatives of the pharmaceutical industry, and patient advocacy groups.

The guidance reiterates the superiority of OS as an endpoint, while also acknowledging the pragmatic difficulties associated with its use, and notes the increasing acceptance of surrogate endpoints in ovarian cancer trials. Other recommendations made in the SGO guidance include the enrollment of smaller, more histologically and molecularly homogenous patients in trials, and the deployment and validation of composite endpoints to integrate multiple traditional endpoints into a single metric.

Gynecologic cancers are devastating to the women who are diagnosed with them by threatening not only their current health but also their ability to conceive and give birth in the future. While significant progress has been made in reducing the incidence of cervical carcinoma with widespread screening and HPV vaccination, the rates of the other gynecologic cancers have remained steady in recent decades. The small numbers of patients affected, relative to other malignancies, and the heterogeneity of these cancers have slowed progress on large clinical trials, hampering efforts to develop new treatments.

Survival rates for ovarian cancer have improved incrementally since the 1990s, but the disease continues to pose a significant mortality threat to patients. Improved understanding of the importance of the tumor microenvironment has led to the development of potent antiangiogenic agents that are effective in a range of solid tumors, and these drugs have become a compelling new option in advanced and recurrent ovarian cancer. Though questions remain regarding the benefit of antiangiogenic therapy to OS, emerging biomarkers that can stratify patient populations may soon allow clinicians to administer this new treatment modality to those who are most likely to benefit.

In addition to antiangiogenic drugs, promising results from trials with PARP inhibitors, immunotherapies, and repurposed drugs offer the potential for improved treatment on several fronts for patients. The shift away from systemic cytotoxic chemotherapy and radiation toward more targeted strategies in other malignancies has resulted in improved survival with fewer toxic side effects, and it is hoped that the same will be observed in gynecologic cancers.

The &ldquo;omics&rdquo; revolution in DNA sequencing and RNA detection technologies has produced an extensive list of new candidate biomarkers and the possibility of routinely using profiles of multiple biomarkers that have the potential to improve prognostic power and allow clinicians to match patients to therapies that are most likely to produce positive results. The convergence of new diagnostic tools and new therapeutic agents has raised the prospect that a major improvement in the incidence and care of gynecologic malignancies is imminent.

54. Abu-Rustum N, Chi D, Coleman RL, et al. Summary of the 2014 MD Anderson International Meeting in Gynecologic Oncology: emerging therapies in gynecologic cancer.

Articles

Clinical Articles

Novel antitumor agents are currently being evaluated in clinical trials for use in various gynecological cancers.

Emerging Treatments and Clinical Trials for Gynecologic Cancers

A histologic section showing specifically squamous cell carcinoma in the cervix (Papanicolaou&rsquo;s stain). SOURCE: NCI

This article is part III of a series. View parts I and II:

The search for gynecologic cancer biomarkers that are prognostic or predictive of patient responses to treatment is an active and fruitful area of investigation. As the cost of genetic testing has declined, the possible number of mutations that can be screened has increased dramatically. Also, a better understanding of the interactions between cancers and the immune system has presented new possibilities in the search for clinically useful biomarkers.

MicroRNAs (miRNAs) are a promising new source of biomarkers for gynecologic cancers. Discovered in the early 1990s, miRNAs are noncoding regulatory RNA molecules ranging from 18 to 22 nucleotides long that function in the cell principally by selectively repressing translation or enhancing degradation of target-coding RNA transcripts.

Several characteristics of miRNAs make them attractive candidates as gynecologic cancer biomarkers, including evidence that some function as oncogenes or tumor suppressors and the fact that they can be detected in circulating blood and other bodily fluids.

To date, multiple studies have been published that suggest the expression levels of individual or multiple circulating miRNAs could be used as biomarkers for ovarian, endometrial, and cervical cancers.

These studies identified associations between clinicopathological disease features and the increased or decreased expression of various miRNAs; however, there is little overlap in the various results.

One recently published paper identified increased miR-181a expression as a candidate biomarker for poorer prognosis in advanced EOC and showed a functional role for the transcript in improved cellular survival, migration, invasion, and drug resistance.

The authors suggest that miR-181a and the transforming growth factor-b (TGF-b) signaling pathway are not only potentially prognostic biomarkers for advanced EOC, but also targets of therapy.

genes are tumor suppressors involved in DNA damage repair.

Mutations in these genes are well known as risk factors for developing breast and ovarian cancers; however, recent research suggests that

status is prognostic of survival time in patients with ovarian cancer. A recent retrospective study reported that mutations of either gene are associated with improved short-term survival rates; however, this advantage decreases over time, and

mutations become a liability at 5 years post diagnosis.

status and outcomes found that mutations in either gene were associated with improved PFS and OS versus noncarriers.

These observations may be important for analysis of OS outcomes in long-term trials in ovarian cancer.

In addition to prognosis, there may be a role for BRCA in selecting the most appropriate treatment strategy. A retrospective analysis of a phase II trial evaluating olaparib maintenance therapy in patients with advanced relapsed ovarian cancer found that patients with

mutations were most likely to benefit from the therapy.

Furthermore, it did not matter whether these mutations were germline or somatic. These results are unsurprising considering that PARP inhibitors, such as olaparib, target cells with homologous recombination defects, such as

could be used to identify patients with advanced ovarian cancer who are likely to respond to PARP-inhibitor therapy.

There are many possible individual biomarkers under consideration for gynecologic cancers. The following list of candidate biomarkers is not exhaustive, but intends to provide an overview of some of the current research. Biomarkers relating specifically to targeted treatments that are new to clinical approval, such as antiangiogenic drugs and PARP inhibitors, are not listed here, but are discussed in the &ldquo;Emerging Treatments and Clinical Trials for Gynecologic Cancers&rdquo; section.

A method for determining the likelihood that a pelvic mass is malignant or benign using serum levels of human epididymis protein 4 and CA-125 in conjunction with the Risk of Ovarian Malignancy Algorithm

has been approved by the FDA, but is not recommended by the NCCN guidelines.

GRB2-associated binding protein 2 (GAB2), an adapter protein that activates signaling through phosphoinositide 3-kinase (PI3K), is an oncogene that is duplicated in many ovarian cancers. The presence of amplified GAB2 can indicate responsiveness to PI3K inhibition.

Loss of progesterone receptor is associated with disease progression and decreased patient survival in endometrial cancer. Loss of receptor expression can occur in either the primary tumor or subsequent metastases. The efficacy of treatment with synthetic progesterone depends on progesterone receptor expression, but this is not routinely assayed. For patients who have lost progesterone receptor expression in metastatic lesions, antiproliferative drugs, such as CDK inhibitors like sirolimus, might be effective, although clinical trials will be required to establish their performance in these patients.

In addition to hormone receptors, the mutation or loss of PTEN and activation of signalling through PI3K and KRAS have been identified as biomarkers early in the development of endometrial cancer. Differences in the rate of mutations in KRAS and inflammatory pathways between obese and nonobese patients with precancerous endometrial lesions suggest that different treatment strategies should be pursued in these 2 populations.

43. Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function.

44. Zhao YN, Chen GS, Hong SJ. Circulating MicroRNAs in gynecological malignancies: from detection to prediction.

45. Parikh A, Lee C, Peronne J, et al. microRNA-181a has a critical role in ovarian cancer progression through the regulation of the epithelial-mesenchymal transition.

46. Yoshida K, Miki Y. Role of BRCA1 and BRCA2 as regulators of DNA repair, transcription, and cell cycle in response to DNA damage.

47. Candido Dos Reis FJ, Song H, Goode EL, et al. Germline mutation in BRCA1 or BRCA2 and ten-year survival for women diagnosed with epithelial ovarian cancer.

48. Zhong Q, Peng HL, Zhao X, Zhang L, Hwang WT. Effects of BRCA1- and BRCA2-related mutations on ovarian and breast cancer survival: a meta-analysis.

49. Foulkes WD. Made-to-measure medicine: BRCA and gynaecological cancer.

50. Moore RG, Miller MC, Disilvestro P, et al. Evaluation of the diagnostic accuracy of the risk of ovarian malignancy algorithm in women with a pelvic mass.

51. Dunn GP, Cheung HW, Agarwalla PK, et al. In vivo multiplexed interrogation of amplified genes identifies GAB2 as an ovarian cancer oncogene.

52. Tangen IL, Werner HM, Berg A, et al. Loss of progesterone receptor links to high proliferation and increases from primary to metastatic endometrial cancer lesions.

53. Berg A, Hoivik EA, Mjos S, et al. Molecular profiling of endometrial carcinoma precursor, primary and metastatic lesions suggests different targets for treatment in obese compared to non-obese patients.

The search for gynecologic cancer biomarkers that are prognostic or predictive of patient responses to treatment is an active and fruitful area of investigation.



Emerging Biomarkers for Gynecologic Cancers

This article is part II of a series. View part I:

Evolving Paradigms in Gynecologic Cancer: Introduction > >

Screening techniques for use in the general population have long been available for cervical cancer and are being actively developed for ovarian cancers. Early and accurate detection of these cancers is key to reducing mortality and increasing survival time in patients. However, the benefits of screening must be weighed against the potential harm of initiating unnecessary medical treatments due to false positives or detection of transient neoplasias. This task is both helped and hindered by the link between HPV infection and some gynecologic cancers, because these infections often spontaneously clear and do not progress to malignant pathology. The latest science and published guidelines for gynecologic cancer screening are reviewed in subsequent sections of this supplement.

Early-stage cervical cancer is often asymptomatic or characterized by symptoms that are not discerned by the patient, including watery vaginal discharge or intermittent spotting. Regular screening is therefore crucial for detecting patients with cervical cancer as early as possible.

The Papanicolaou cytological test (Pap smear) has long been used to identify preinvasive cervical lesions and early-stage cancer. This test can be conducted in 2 formats of equivalent efficacy: conventional cytology, in which cells are spread on a glass slide, or liquid-based cytology, in which the collected cells are suspended in a vial of preserving fluid.

The other primary method of cervical cancer screening is DNA testing for the presence of HPV infection, although this test should only be conducted on patients over the age of 30 years, because the high rate of infection in younger women may lead to overtreatment.

Table 2. Current Cervical Cancer Screening Guidelines

Conventional Pap or liquid cytology test every 3 years

HPV test and Pap smear cotest every 5 years

Stop screening if prior negative result and not at high risk

No screening if cervix removed and no prior high-grade precancer or cervical cancer

Positive cytological screening tests should indicate a diagnostic follow-up by colposcopy, endocervical curettage, or biopsy.

Current guidelines issued by the American Cancer Society, the American Society of Colposcopy and Cervical Pathology, and the American Society for Clinical Pathology are shown in

The early detection of EOC can significantly impact prognosis, as the 5-year survival rate for patients who receive treatment for stage 1 disease is >90%, but this figure plunges to less than 40% for those with advanced-stage disease.

Due to the heterogeneity of ovarian cancer, however, effective screening strategies have yet to be developed, and the majority of patients are diagnosed with malignancies in advanced stages.

Several prospective trials have been conducted to investigate potential screening strategies using combinations of physical examination, ultrasound imaging, and detection of cancer antigen 125 (CA-125). The Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial used a protocol that combined testing of serum levels of CA-125 with transvaginal ultrasound imaging and reported no reduction in ovarian cancer mortality and increased risk of complications from false-positive results.19 These results led the US Preventive Services Task Force to recommend against screening for ovarian cancer in low-risk populations.20 A similar trial in a larger cohort, the United Kingdom Collaborative Trial of Ovarian Cancer Screening is ongoing, with mortality data expected in 2015.

At present, screening is not recommended by any professional body, although some clinicians use CA-125 levels and transvaginal ultrasound to monitor patients at high risk (eg, family history, BRCA mutations).

There is no routine screening method available for uterine cancer. Unlike ovarian cancer, however, early-stage endometrial cancer is symptomatic, causing irregular vaginal bleeding in a patient population that is primarily postmenopausal, and patients therefore frequently seek care and are diagnosed at a treatable stage.6 The fact that most patients are diagnosed at an early stage and with localized disease contributes to a relatively high survival rate for this cancer, although the mortality rate has increased more quickly than the incidence rate in recent years.

Early-stage vaginal cancer often does not have symptoms that cause a patient to seek medical care, and is therefore usually diagnosed at an advanced stage. A Pap test is capable of identifying early-stage disease because cells of the vaginal lining are sometimes inadvertently included in the sample when cervical samples are collected, and precancerous and early-stage abnormalities in these vaginal cells may then be observed. Because cervical cancer is so much more common than vaginal cancer, however, intentional collection of cells from the vaginal wall is not a routine practice.

Because it affects an external bodily structure, visual changes associated with the development of vulvar cancer are often identified at a relatively early stage by patients, who then seek medical care. The other primary means of early detection of vulvar cancer is a routine pelvic examination during a gynecologic exam.

Infections by HPV do not normally cause serious pathology in women and are most often spontaneously cleared. However, some cases result in persistent infection lasting many years and eventually lead to transformation and the development of cervical cancer and, to a lesser extent, vaginal and vulvar cancer. Therefore, HPV vaccines have been developed both as prophylactic measures to prevent initial infection and as therapeutic tools to promote clearance of persistent infections.

Several years after the initiation of HPV vaccination programs in Australia and Denmark, investigators observed a significant reduction in the number of precancerous cervical abnormalities,25,26 indicating that this strategy will prove effective in reducing the incidence of cervical cancer in the general population. As of 2013, use of HPV vaccinations in the United States is low, with 57% of girls and 35% of boys having received at least one dose of the vaccine, and completion rates being lower than that.

There are currently 2 HPV vaccines approved by the US Food and Drug Administration (FDA): a quadrivalent vaccine (Gardasil) that protects against HPV types 6, 11, 16, and 18, and a bivalent vaccine (Cervarix) that targets HPV types 16 and 18. Guidelines published in 2014 by the Advisory Committee for Immunization Practices recommend that girls 11 to 12 years old should be routinely vaccinated using either the bivalent or quadrivalent vaccine. Older girls and women (13 to 26 years old) who have not received or completed the vaccine series should also be vaccinated.

Therapeutic vaccines to promote the clearance of ongoing persistent HPV infections are currently under development. One such effort used a DNA vaccine to induce T-cell immunity directed against the HPV E6 and E7 antigens in 9 out of 9 patients in the study.

Importantly, this immune activation resulted in viral clearance and regression of neoplastic lesions in 7 of these patients, demonstrating the feasibility of such a treatment strategy in the future.

Several different treatment options are available for gynecologic cancers depending on the stage and the specific type of cancer concerned. In 2014, the treatment of advanced, recurrent cervical and ovarian cancers experienced a significant change due to the FDA approval of the antiangiogenic drug bevacizumab. The August approval for late-stage cervical cancer was the first since the combination of topotecan with cisplatin received approval in 2006, while bevacizumab became the first new drug approved for recurrent ovarian cancer in more than 15 years. These approvals also represented firsts for targeted therapy for gynecologic cancers and a brand new avenue for treatment of these diseases.

Broadly, approved treatments for gynecologic cancer include surgery, chemotherapy, radiotherapy, and antiangiogenic therapy. Recommendations for the treatment of several types of gynecologic cancer have been published in guidelines developed by the NCCN.

Surgical resection of the affected tissue is recommended for patients with early-stage disease (in situ or stage 1A), including conization or trachelectomy in patients wishing to preserve fertility or hysterectomy for older patients and those unconcerned with sparing fertility.

Lymphadenectomy may also be appropriate if pelvic lymph nodes are involved. Internal radiation therapy is an option for patients who are not candidates for surgery. Concomitant radiotherapy and cisplatin-based chemotherapy or neoadjuvant chemotherapy is recommended in the NCCN practice guidelines for patients with more advanced disease.

In August 2014, the FDA approved the antiangiogenesis drug bevacizumab, an antibody targeting the angiogenic signaling molecule vascular endothelial growth factor A (VEGF-A), for use in combination with chemotherapy for the treatment of persistent, recurrent, and metastatic cervical cancer. This approval was based on data from the phase III GOG 240 trial that demonstrated that adding bevacizumab to either cisplatin-paclitaxel or topotecan-paclitaxel chemotherapy significantly increased OS and response rates in patients with recurrent, persistent, or metastatic cervical cancer.

For treatment of early-stage ovarian epithelial cancer (stage 1), surgical resection alone is often appropriate and should include hysterectomy, bilateral salpingo-oophorectomy, and omentectomy. Unilateral salpingo-oophorectomy, a fertility sparing procedure, has been reported to be comparable in outcome to radical resection in patients who are &le;40 years old, undergo comprehensive surgical staging, and have one disease-free ovary.

Though rare in comparison to EOC, ovarian cancer also occurs as malignant germ cell tumors, including dysgerminomas, immature teratomas, embryonal tumors, and endodermal sinus (yolk sac) tumors. These cancers are primarily diagnosed at an early stage in relatively young women (&le;35 years); therefore, the 5-year survival rates are >95% for patients with stage 1 tumors and >70% for those with advanced disease.

The primary treatment for malignant germ cell tumors is surgical resection. In patients with stage 2 to 4 disease, additional postoperative chemotherapy with bleomycin/etoposide/platinum is recommended.

Patients with stage 2, 3, or 4 EOC at diagnosis can be treated with cytoreductive surgery and adjuvant chemotherapy with platinum-based regimens that may be combined with alkylating agents or paclitaxel depending on patient characteristics and optimal toxicity profile.

In cases of recurrent EOC that is resistant or refractory to platinum-based agents, recommended drugs include docetaxel, oral etoposide, gemcitabine, liposomal doxorubicin, weekly paclitaxel, and topotecan.

Bevacizumab has been frequently used off-label by clinicians to treat ovarian cancer in the past.

The interest in bevacizumab in treating ovarian cancer has been driven by the known importance of angiogenic pathways in EOC and the efficacy reported in other solid tumors.

Two phase III trials (GOG-0218 and ICON7) have investigated the efficacy of bevacizumab as an adjuvant to a carboplatin/paclitaxel chemotherapy regimen as first-line therapy in EOC,33 and the data demonstrated increased progression-free survival (PFS) in patients who received bevacizumab, although there was no evidence of increased OS or quality of life. Therefore, the NCCN guidelines include category 3 recommendations for the use of bevacizumab, according to the ICON7 and GOG-0281 regimens, as an adjuvant in first-line treatment of EOC and as maintenance therapy.

Two other phase III trials have examined the efficacy of bevacizumab in recurrent EOC that is both platinum-resistant (AURELIA)

The results have demonstrated a benefit to PFS when bevacizumab is combined with either platinum-based or nonplatinum chemotherapies, and the NCCN recommends both of these protocols for recurrent ovarian cancer. Additionally, on November 14, 2014, the FDA approved the combination of bevacizumab with nonplatinum chemotherapy (pegylated liposomal doxorubicin, weekly paclitaxel, or topotecan) for use in recurrent, platinum-resistant disease on the basis of results from the AURELIA trial. In the trial, bevacizumab improved PFS in all chemotherapeutic regimens, and the greatest increase was observed in the cohort receiving weekly paclitaxel, although the inter-cohort results were not significant.

On December 19, 2014, the FDA approved the poly ADP-ribose polymerase (PARP) inhibitor olaparib for treating advanced ovarian cancer. Drugs in this family target cells with deficiencies in DNA repair pathways, including mutations in the breast cancer 1, early-onset (BRCA1) and breast cancer 2, early-onset (BRCA2) genes that are observed in 10% to 15% of all patients with ovarian cancer. The FDA decision was based on trial data showing improved objective response rates in patients with BRCA mutations, and the approval applies to patients with such mutations who have already received at least 3 previous chemotherapy treatments.

The most common type of uterine cancer, endometrial cancer (EC), can be treated surgically with hysterectomy and bilateral salpingo-oophorectomy if it is diagnosed at an early stage and is localized. Pelvic lymphadenectomy and postoperative radiation therapy may also be necessary. In highly selected patients with early-stage EC, treatment with progestins, such as megestrol acetate or medroxyprogesterone, is a fertility-sparing alternative to surgery.

Adjuvant chemotherapy or radiation is recommended for patients with advanced or extrauterine disease. Surgery, chemotherapy, radiation, and hormone therapy with progestational agents are all recommended options for recurrent or metastatic EC.

Uterine serous adenocarcinomas, clear cell adenocarcinomas, and carcinosarcomas are all more aggressive variants of uterine cancer and are treated with surgical resection and highly individualized adjuvant therapy. Platinum-based and taxane-based therapy is recommended for patients with uterine serous adenocarcinoma and clear cell adenocarcinoma, and ifosfamide-paclitaxel chemotherapy is recommended for carcinosarcomas.

The primary treatment for vulvar carcinoma at all stages is surgical resection with radiation integrated into treatment for cases of stage 3 or stage 4 cancer.

Newer regimens have been developed using neoadjuvant or primary chemoradiation, though these approaches have not been standardized, nor have they been shown to be more effective or safe than primary surgery.

The rarity of vaginal carcinoma has constrained the ability of investigators to conduct prospective studies and develop standard therapy protocols for this cancer. Surgical resection and radiation are often curative in early-stage disease, and radiotherapy is standard care at later stages, though survival rates are lower than those achieved in cervical cancer.

Concurrent chemotherapy, including cisplatin and 5-fluorouracil (5-FU), is sometimes administered on the basis of the treatment&rsquo;s efficacy in cervical cancer, and there is evidence of potential benefits of this treatment in increased OS and disease-free survival (DFS).

Further investigation is required to verify these benefits, however.

< < < Evolving Paradigms in Gynecologic Cancer: Introduction

More from this project will be coming soon.

14. Arbyn M, Bergeron C, Klinkhamer P, Martin-Hirsch P, Siebers AG, Bulten J. Liquid compared with conventional cervical cytology: a systematic review and metaanalysis.

15. McGraw SL, Ferrante JM. Update on prevention and screening of cervical cancer.

16. National Cancer Institute. PDQ&reg; Cervical Cancer Treatment. PDQ Cancer Information Summaries http://cancer.gov/cancertopics/pdq/treatment/cervical/HealthProfessional. Accessed November 8, 2014.

17. Saslow D, Solomon D, Lawson HW, et al. American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer.

18. American Cancer Society. Survival rates for ovarian cancer, by stage. http://www. cancer.org/cancer/ovariancancer/detailedguide/ovarian-cancer-survival-rates. Accessed November 19, 2014.

19. Buys SS, Partridge E, Black A, et al. Effect of screening on ovarian cancer mortality: the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Randomized Controlled Trial.

20. Moyer VA, Force USPST. Screening for ovarian cancer: U.S. Preventive Services Task Force reaffirmation recommendation statement.

21. Sharma A, Apostolidou S, Burnell M, et al. Risk of epithelial ovarian cancer in asymptomatic women with ultrasound-detected ovarian masses: a prospective cohort study within the UK collaborative trial of ovarian cancer screening (UKCTOCS).

22. National Cancer Institute. PDQ&reg; Ovarian Epithelial Cancer Treatment. PDQ Cancer Information Summaries http://cancer.gov/cancertopics/pdq/treatment/ovarianepithelial/HealthProfessional. Accessed November 8, 2014.

23. Ueda SM, Kapp DS, Cheung MK, et al. Trends in demographic and clinical characteristics in women diagnosed with corpus cancer and their potential impact on the increasing number of deaths.

24. Aggarwal P. Cervical cancer: Can it be prevented?

25. Baldur-Felskov B, Dehlendorff C, Munk C, Kjaer SK. Early impact of human papillomavirus vaccination on cervical neoplasianationwide follow-up of young Danish women.

26. Crowe E, Pandeya N, Brotherton JM, et al. Effectiveness of quadrivalent human papillomavirus vaccine for the prevention of cervical abnormalities: case-control study nested within a population based screening programme in Australia.

27. Cifu AS, Davis AM. Use of HPV vaccine in males and females.

28. Kim TJ, Jin HT, Hur SY, et al. Clearance of persistent HPV infection and cervical lesion by therapeutic DNA vaccine in CIN3 patients.

Screening techniques for use in the general population have long been available for cervical cancer and are being actively developed for ovarian cancers.

Detection, Prevention, and Current Treatment Strategies in Gynecologic Cancers

FIGURE 1. The annual impacts of the 3 major gynecologic cancers are shown in terms of incidence, mortality, and health care cost.

Numbers for new cases and deaths are estimates for 2014

New cases and deaths are estimates for 2014.

Costs are estimates of national expenditures in 2010.

In the past decade, there has been a rapid increase in the understanding of how various cancers develop and progress. This new knowledge has led to the advance of novel and more targeted strategies for the prevention, diagnosis, and treatment of many malignancies, including gynecologic cancers.

Gynecologic cancers include 5 main cancers occurring in the female reproductive system: cervical, ovarian, uterine, vaginal, and vulvar. Malignancies in each of these sites can be of multiple histological types, so that the group of diseases encompassed by the term &ldquo;gynecologic cancers&rdquo; is large and heterogenous. Collectively, these cancers had an estimated incidence in 2014 of 95,000 new cases in the United States and nearly 29,000 deaths. Uterine cancer is the most commonly diagnosed gynecologic cancer, accounting for over 55% of new diagnoses in 2014, while ovarian cancer is the most lethal, comprising nearly 50% of deaths from gynecologic malignancies (

Because of newer methods that enable the early detection and prevention of cervical cancer, both the incidence and mortality rates for this disease declined by about 50% between 1975 and 2011. In contrast, reductions in the incidence and mortality for uterine and ovarian cancer have been much more modest, due in large part to incremental improvements in care rather than drastic shifts in treatment paradigms,

while incidence and mortality rates of the much more rare vaginal and vulvar cancers have remained largely static for the past 30 years.

Ovarian cancer is the most deadly gynecologic neoplasm and is the fifth leading cause of cancer death in women in the United States.

The majority of malignancies that arise from the ovaries tend to be epithelial cancers (90%). Fallopian tube cancers and primary peritoneal cancers are uncommon gynecologic cancers that are also epithelial in nature and are addressed with the same therapeutic strategies as epithelial ovarian cancer (EOC). The histopathologies of the remaining 10% of cases of ovarian cancer are ovarian low malignant potential tumors (also known as borderline epithelial ovarian tumors), malignant germ cell neoplasms, carcinosarcomas, and malignant sex cord-stromal tumors.

The majority of uterine malignancies are adenocarcinomas, which are also referred to as endometrial cancer. Endometrial cancer is the most common cancer of the female genital organs in the US.

Other less common types of uterine cancer include uterine serous adenocarcinomas, clear cell adenocarcinomas, sarcomas, and epithelial tumors, which are more aggressive and are managed differently from adenocarcinomas.

The most important factor driving the development of cervical cancer is infection by the human papilloma virus (HPV). This fact is demonstrated by the correlation observed between the rate of HPV infection and the incidence of cervical cancer across different countries and geographical areas.

While the incidence of cervical cancer has decreased significantly in countries with screening and vaccination programs in place, it remains a major cause of mortality in women in developing countries.

Approximately 80% of all cervical cancers are squamous cell carcinomas, while the remaining 20% are mainly adenocarcinomas.

Tumors of the vagina that involve the cervix of women with an intact uterus are also usually classified as cervical cancers.

The bulk of the decline in the incidence of cervical cancer overall is accounted for by a decline in squamous cell carcinoma; however, cases of cervical adenocarcinoma have increased in recent years, possibly due to a failure of cytological screening methods to detect adenocarcinoma. The recent implementation of HPV-based testing and vaccination may correct this imbalance due to their respective abilities to effectively detect and prevent both types of cervical cancers.

In the past decade, there has been a rapid increase in the understanding of how various cancers develop and progress.

Gynecologic Cancer | Evolving Paradigms

Emerging Treatments and Clinical Trials for Gynecologic Cancers

Emerging Biomarkers for Gynecologic Cancers

Detection, Prevention, and Current Treatment Strategies in Gynecologic Cancers

Evolving Paradigms in Gynecologic Cancer: Introduction