By Mari Hoffman, Genetics & Genomics ‘21
Author’s note: I wrote this literature review for an assignment in UWP104E, Writing in Science. I chose this topic because my mom recently got diagnosed with ovarian cancer and I wanted to use this opportunity to learn more about the literature surrounding ovarian cancer and more specifically the latest research in diagnostics and treatments of ovarian cancer.
Eighty percent of ovarian cancers are diagnosed at a late stage of either three or four [1,2]. This is due to the nature of the disease to appear asymptomatic in many women, preventing early diagnosis [3,4]. Early diagnosis is also difficult to obtain due to the lack of biomarkers with high sensitivity and effective diagnostic testing for early disease detection [2,4]. New diagnostics markers and techniques are being developed such as the use of circRNAs, which are single-stranded circular mRNA transcripts,  and novel biomarkers such as ROMA and RMI . The common late state diagnosis of the disease contributes to the fact that ovarian cancer also has the highest mortality rate among gynecological cancers [2,4,5]. Ovarian cancer represents the 7th most common cancer  and women in the United States have an average lifetime risk of 1.3% of developing ovarian cancer . Ovarian cancer encompasses a larger group of malignancies that vary in origin, grade, and histology [1,2,6]. Although for the purpose of this review, when discussing ovarian cancer, I am referring to the most common type which is high-grade serous ovarian cancer [1,2,6,7].
Initial treatment of Ovarian cancer typically starts with either cytoreductive surgery or platinum-based chemotherapy, depending on the degree of the cancer spread. The combination of the two treatments, regardless of the order, has been the standard of care (SOC) for ovarian cancer [2,7]. Although most patients respond initially to this SOC treatment, the rate of recurrence of ovarian cancer is around 70 percent [2,5,7]. Due to the high rate of recurrence, the advancement of novel and targeted treatment is needed. It is important to consider the disease’s genetic features and molecular profile to understand the targeted therapies that are available to those with ovarian cancer. Some of the most promising targeted treatments have been with the use of PARP inhibitors [2,5,7]. Other targeted therapies are under exploration to be used in conjunction with chemotherapy such as Bevacizumab [2,7]. This review will examine and evaluate the current options and limitations of diagnostic screening and explore secondary treatments of ovarian cancer.
Diagnostics of Ovarian Cancer
Overview and Limitations of Current Diagnostic Techniques
Diagnostic testing and screening play an extremely important role in ovarian cancer prognostics because the earlier the cancer is found, the higher the likelihood of the patient having a positive outcome [4,8]. Cancer prognostics predict the likely course of a disease. Unfortunately, there are no highly effective biomarkers that are used preventively in the diagnostics of ovarian cancer [2,4,8,9]. The most common method for the detection of ovarian cancer is the use of transvaginal ultrasonography and cancer antigen 125 (CA125) level measurement [1,3,4]. CA125 is a membrane glycoprotein antigen that has elevated expression levels in ovarian cancer [2,4]. CA125 is not very effective for early detection of ovarian cancer, such as stage 1, as the sensitivity of CA125 is reported to be under 50% . CA125 sensitivity was found to be around 80-90% in the advanced stage of the disease . Although CA125 has downfalls as a diagnostic marker, it is also used as a prognostic marker to assess response to treatment and recurrence of the disease [2,6]. Transvaginal ultrasonography has been shown to be a more useful diagnostic technique overall when used in combination with CA125 testing due to the high rate of false positives [4,10]. The false positives come from the low specificity of the ultrasound to be able to detect malignant versus benign abnormalities. Also, transvaginal ultrasonography is not always able to detect a tumor prior to metastasis .
Since there is no single biomarker that is highly effective in detecting ovarian cancer, detection markers have been combined and used algorithmically for higher sensitivity and specificity. It is important to understand that these tests are not true diagnostic tests, but are used to determine the likelihood of malignancy and the extent of the spread of the disease [8,9]. Some examples of algorithms being used for diagnostic testing are the Risk of Ovarian Malignancy Algorithm (ROMA)  and Risk of Malignancy Index (RMI) . RMI is a mathematical formula that incorporates information from CA125 levels, ultrasounds findings, and menopausal status to quantify a score that is used to evaluate the risk of malignancy . ROMA is a new algorithm that was proposed in 2009 that combines the use of human epididymis protein 4 (HE4) and CA125 levels [8,9]. HE4 is overexpressed in serous ovarian cancer with a sensitivity of around 76.5% when it is combined with CA125 [4,8]. The ROMA algorithm was a significant improvement in initial diagnostic testing compared to single biomarker tests because of the increase in sensitivity, but is typically not used until a symptom or sign of ovarian cancer is present [8,9]. Overall, there is currently a combination of biomarkers that are used for diagnostic and prognostics of ovarian cancer yet there is a need for higher specificity and sensitivity of these tests. With more sensitive biomarkers, diagnosis of ovarian cancer before the presence of the disease would yield a much better prognosis for patients.
Novel Diagnostic Testing
Most of the diagnostic testing described above are protein-based markers. More recent research explores the use of nucleic acids as novel serum markers, which have the potential to yield higher specificity and sensitivity than protein-based biomarkers . One specific kind of nucleic acid that is being explored for the use of diagnostics in ovarian cancer is microRNA (miRNA), a noncoding and single-stranded molecule that ranges from 20-22 nucleotides in length. They are involved in the post-transcriptional regulation of genes which impact a variety of factors relating to cell development, differentiation, and growth. [11,12]. In ovarian cancer, it has been found that miRNAs can play many different roles. Elevated expression levels of certain miRNAs have been associated with tumor progression and are a potential option as a noninvasive diagnostic biomarker [13,14]. Panels of miRNAs have been shown to discriminate between patients with malignant versus benign ovarian disease. A smaller subgroup of these miRNAs can even be used in association with lymph node metastasis and identification of stage three or four presentations of the disease. There is also a correlation between upregulation of certain miRNAs and serum CA125 values . There is a diagnostic value of using miRNAs for the detection of ovarian cancer and is a novel area of research that brings hope to diagnostics of ovarian cancer.
Another novel diagnostic biomarker that is being investigated is the use of circRNAS. CircRNAs are single-stranded circular mRNA transcripts that are a part of the family of long noncoding RNAs. They were originally thought to be functionless byproducts of RNA splicing until they were discovered to play a regulatory role in the progression of tumors found in cancers. In ovarian cancer, circRNAs act primarily as a miRNA sponge, binding to miRNA and therefore inhibiting it from carrying out its desired function. This function contributes to and regulates ovarian cancer cell proliferation and invasion. The elevation of circRNAs in the sera of patients with ovarian cancer shows the potential of circRNA to be an effective diagnostic marker due to its high abundance and stability in ovarian cancer tissues. CircRNA is more stable than linear RNA because it is covalently closed, not containing a 5’ cap or poly-A tail [3,15]. Further research is needed to be done to fully understand the role of circRNAs in ovarian cancer, but the current research shows the great potential of circRNAs to be used as a diagnostic marker.
Current Treatment of Ovarian Cancer
Standard of Care and Limitations
The standard of care (SOC) in the medical world is the treatment process that a physician would advise based on the current knowledge and research surrounding the disease. The treatment of ovarian cancer is personalized to the patient depending on the extent of the spread of the disease. There are defined SOC protocols for each of the varying stages of ovarian cancer. If ovarian cancer is found in the early and localized stage, the SOC is to do surgery in an attempt to eliminate the cancer cells present in the area. Unfortunately, ovarian cancer is most commonly diagnosed in the advanced stage. The SOC of advanced-stage ovarian cancer is to conduct surgery if possible and platinum-based chemotherapy. The guidance of whether to start with surgery or chemotherapy is based on whether there is evidence of metastatic disease or not. If there is no evidence of metastatic disease, it is recommended to first undergo surgery. Surgery is primarily used when the cancer is limited to the abdomen area and is localized. However, if the disease has metastasized then typically chemotherapy is the first line of defense [2,7,16]. The ability of surgery to reduce the likelihood of residual disease when the cancer has spread remains controversial. The most important factor in surgery having a positive impact is the extent that the disease has spread. It is found that if patients have a low or moderate disease preoperatively, compared to extensive, then the approach to start with surgery remains important .
A hallmark of cancer is that cells are able to divide rapidly and evade normal cell death. Chemotherapy is a treatment that uses drugs that kill rapidly dividing cells. The use of platinum-based carboplatin and taxol to treat advanced ovarian cancer is the standard [16,17]. This standard chemotherapy consists of intravenous carboplatin and taxol every three weeks. Another treatment option that is being explored is a dose-dense therapy regimen. This type of therapy gives the same dose of intravenous chemotherapy compared to standard chemotherapy, but with less time in between the intervals. The idea is that highly aggressive cancers, like ovarian cancers, could have less regrowth if there are shorter cycles in between treatments. Although there is support in real-world data that dose-dense therapy improves overall survival, randomized trials found no significant difference [18,2].
Ifosfamide-based regimens are also used in current treatments of ovarian cancer. Ifosfamide is in the nitrogen mustard family of medications which was the first chemotherapy drug. Patients can be chemotherapy-sensitive or chemotherapy-resistant. Having sensitivity towards a chemotherapy treatment means that the patient’s cancer is responsive to the chemotherapy treatment. It has been demonstrated that patients are more sensitive to ifosfamide-based regimens as opposed to platinum-based therapies. Although there is higher sensitivity to the treatment, ifosfamide-based therapy has a higher toxicity effect than platinum-based therapies. The patient’s response to platinum-based chemotherapy is typically assessed first and ifosfamide therapy can be used if there is no response to platinum-based chemotherapy [16,20].
The prognosis of patients with advanced ovarian cancer even with the SOC remains poor. As mentioned previously, the late-stage diagnosis of the disease and high recurrence rate leaves therapeutic strategies to treat ovarian cancer a challenge .
Novel Targeted Therapies
Currently, targeted treatments are used as second-line therapy for ovarian cancer. This is due to the recent and novel use of targeted therapies in the treatment of ovarian cancer. Targeted agents have only been used in clinical trials relatively recently compared to the SOC treatments of ovarian cancer. Due to this reason, and the aggressive nature of ovarian cancer, targeted therapies are typically only used as a secondary treatment [2, 7,16]. There is recent research indicating the potential use of targeted therapies as a first-line treatment, but more research is needed at this time in order to establish targeted therapies as a new standard of care [5,7].
BRCA ½ mutations are present in about 18% of high-grade serous ovarian cancer and guide what treatment options are available. The BRCA1 and BRCA2 genes are tumor suppressor genes and are involved in the repair of DNA double-stranded breaks (DSB) through the use of the error-free Homologous Recombination (HR) pathway. If an individual has a mutation in BRCA ½ then the error-prone nonhomologous end-joining (NHEJ) pathway is used to repair the DSBs and can result in the formation of cancer cells. PARP inhibition is a treatment option that is targeted for individuals harboring the BRCA ½ mutation. Poly(ADP-ribose)polymerase (PARP) are enzymes that function to repair single-stranded breaks (SSBs) in DNA through the use of the Base Excision Repair (BER) pathway. When PARP is inhibited, the repair of the SSBs in DNA can not be completed which results in the formation of DSBs at the replication fork. This formation is toxic to the cell and when not resolved, it causes cell death. It has been found that when a patient has a BRCA mutation or PARP inhibition independently, there are no detrimental effects to the cells. It is when there is a combination of a BRCA mutation and PARP inhibition, that there is no recovery of the cell and the cell demonstrates a synthetic lethality phenotype [5,7].
The first PARP inhibitor to be approved for patients with germline BRCA1/2 mutations with high-grade ovarian cancer was Olaparib. It has been approved for patients who have undergone three or more first-line treatment of chemotherapy and for patients who are undergoing maintenance therapy after having a complete or partial response to platinum chemotherapy. Patients who are using Olaparib as maintenance therapy do not have to have BRCA1/2 mutation status, although there is a higher objective response rate in those who are BRCA1/2 mutated. The proportion of patients who have had a cancer-free event when using Olaparib twice daily compared to a placebo show a significant increase in overall survival. PARP inhibitors open up a new paradigm of treatments for patients with ovarian cancer and are currently undergoing clinical trials as a first-line treatment [5,7].
Bevacizumab, also known as Avastin, is a monoclonal antibody that has been used as a treatment for ovarian cancer in conjunction with carboplatin and taxol chemotherapy. It is also an anti-angiogenesis agent that acts to prevent carcinogenesis by inhibiting the creation of new blood vessels for the cancer. Randomized trials have shown improved progression-free survival rates with the addition of Bevacizumab to the standard chemotherapy. Although findings support that there is no overall survival rate increase with the addition of Bevacizumab , there are also additional toxicities from Bevacizumab such as hypertension and delayed wound healing . These are all important factors to consider when evaluating treatment options.
Ovarian cancer today remains the deadliest disease among gynecological malignancies [2,4,5]. This review highlights the critical importance for researchers to create more effective diagnostics for earlier detection of the disease and cancer in general. The future of diagnostics is moving towards personalized testing and screenings of multiple types of cancers based on unique genetic profiles. While there are many novel targeted therapies being explored, it is imperative that the research on treatments of the disease continue to evolve and improve. Although the diagnosis of ovarian cancer remains serious, there is hope that the use of novel diagnostic techniques and targeted therapies such as PARP inhibitors and Bevacizumab, improves the outcomes of patients with the disease.
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Hard Copy Publication References
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