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The ovaries are the female reproductive organs that produce eggs. Ovarian cancer refers to the cancerous changes that occur in the ovaries. It is a tumor caused by abnormal, uncontrollable reproduction of certain cells in the ovary. Ovarian cancer is a common female reproductive system tumor with a high incidence, second only to cervical cancer and endometrial cancer. Its mortality rate ranks the first among gynecological tumor mortality [1].
Figure 1 Ovarian cancer
1. Histological Classification of Ovarian Cancer
3. Risk Factors for Ovarian Cancer
According to the origin of tumor cells, ovarian cancer can be divided into three types: epithelial tumor, stromal tumor and germ cell tumor.
Epithelial tumors are derived from the germinal epithelium of the ovary, which is the predominant form of ovarian cancer. About 90% of ovarian cancers are epithelial tumors. These tumors may be benign or malignant.
This ovarian cancer is derived from the specific sex stroma of the ovary and is therefore also called sex stromal tumor. About 7% of ovarian cancers are stromal tumor. It includes granulosa cell tumor, theca cell tumor, fibroma, androblastoma, gynandroblastoma and the like. In general, theca cell tumor and fibroma are benign tumors, others are low-grade malignant tumors.
Germ cell tumors are derived from germ cells of the ovary. It usually happens to young people. In addition, there are metastatic tumors, which refer to malignant tumors originating from other organs, including the digestive tract and other organs of the gynecology.
Among ovarian cancer, 90% to 95% are primary ovarian cancers, and only 5% to 10% are metastatic ovarian cancer.
There are almost no symptoms in the early stage of ovarian cancer, and even if there are symptoms, it is not specific. It’s difficult to diagnosis it in the early stage of ovarian cancer. When receiving treatment, 60% to 70% of patients are in advanced stages.
This seriously affects the survival of patients with ovarian cancer. Therefore, ovarian cancer is also known as the "silent killer".
Symptoms in the early stages of ovarian cancer are often vague and can easily be attributed to other causes. So if these symptoms appear, you should be alert to whether it is related to ovarian cancer.
Early signs of ovarian cancer include bloating, abdominal and/or pelvic pain, fatigue and shortness of breath [2], lower body pain, lower abdominal pain, back pain, indigestion or heartburn, rapid satiety when eating, frequent and urgent urination, painful intercourse, and changing bowel habits, such as constipation. As ovarian cancer progresses, it can also cause nausea, weight loss and loss of appetite.
If these symptoms occur frequently, you need to see a doctor as soon as possible.
Figure 2 Sign and symptom of ovarian cancer
The cause of ovarian cancer is unclear. However, genetic factors, reproductive factors, environmental factors and lifestyle factors may all play a role.
In ovarian cancer studies, BRCA1 and BRCA2 mutations are the most important known genetic risk factors for ovarian cancer, with up to 17% of patients having these two mutations [3]. The risk of ovarian cancer in ordinary women is only about 1%, while the risk of ovarian cancer in BRCA1 and BRCA2 germline carriers is 54% and 23%, respectively, which is a high-risk group for ovarian cancer. Besides BRCA1 and BRCA2, many genes increase the risk of ovarian cancer. For example, RAD51C, RAD51D, BRIP1, BARD1 and PALB2 [4] [5]. In addition, CHEK2, MRE11A, RAD50, ATM and TP53 may also increase the risk of ovarian cancer.
Compared with other women, the incidence of ovarian cancer increased significantly in women with a family history of ovarian cancer, breast cancer, endometrial cancer, and colorectal cancer. For these people, genetic screening can be used to determine whether someone carries a gene associated with an increased risk.
Women diagnosed with breast cancer are at higher risk for ovarian cancer.
Compared with women who did not give birth, women who gave birth had a reduced risk of all subtypes of ovarian cancer, with the most significant reduction in the risk of clear cell carcinoma.
Multiple pregnancies, breastfeeding and oral contraceptives may reduce the risk of ovarian cancer. Women who took oral contraceptives for 5-9 years reduced their risk by about 35 percent. Oral contraceptives have been shown to reduce the risk of ovarian cancer in individuals with germline BRCA1 mutations and those without genetic predisposition [6].
People with a history of infertility have an increased risk of ovarian cancer, and infertility treatment may also increase the risk.
Continuous ovulation causes continuous damage and repair of the ovarian surface epithelium, which may lead to ovarian cancer. There is a correlation between the total number of ovulations in women's lifetime and the risk of ovarian cancer. The use of ovulation drugs can increase the risk of ovarian tumors.
Some studies have shown that tubal ligation can significantly reduce the risk of ovarian cancer by up to 70%.
HRT increases the risk of ovarian cancer in postmenopausal women [7]. The longer the HRT lasts, the greater the risk, and once the treatment is stopped, the risk returns to normal.
Endometriosis is a disease in which endometrial tissue-like tissue grows outside the uterus. Women with endometriosis have a 30% higher risk of ovarian cancer than other women.
Although ovarian cancer can occur at any stage of a woman's life, most ovarian cancer occurs in women over the age of 65. In about 90 percent of cases, ovarian cancer occurs after age 40, and most cases after age 60.
People who are obese or overweight have a higher risk of cancer. Studies have shown that obesity is also a possible risk factor for ovarian cancer after menopause [8].
Epidemiological data suggest that various physical or chemical products of the industry may be associated with the onset of ovarian cancer.
In addition, studies have investigated the relationship between dietary factors and the risk of ovarian cancer in the general population. Whether the incidence of ovarian cancer is related to eating habits or ingredients (high cholesterol levels) is still inconclusive. Other lifestyle factors that may affect the risk of ovarian cancer include the use of talcum powder and non-steroidal anti-inflammatory drugs, and smoking.
Figure 3 Risk factors for ovarian
The typical symptoms of ovarian cancer are not obvious in the early stage, and there is still no proper screening method, which leads to its high mortality rate, making it the third most malignant tumor in the female reproductive system. Finding effective methods for early diagnosis and improving the specificity of diagnosis are the focus of ovarian cancer diagnostic research.
The following tests are used to diagnose ovarian cancer:
Blood test: Tumor marker CA125 and human epididymis protein 4 (HE4) are the most valuable tumor markers in ovarian epithelial cancer.
However, CA125 level is also increased in some non-ovarian cancer diseases, such as breast cancer, lung cancer, endometrial cancer and some benign ovarian tumors [9]. This indicates that serum CA125 has poor sensitivity and specificity in the diagnosis of ovarian cancer, and the false positive rate is high. Therefore, in the diagnosis of ovarian cancer, the detection of CA125 level has certain limitations. The combination of human epididymis protein 4 and CA125 can provide a higher diagnostic rate for ovarian cancer. HE4 is a glycoprotein expressed in epithelial carcinoma of ovary, which is specific for the diagnosis of ovarian cancer. Ferraro et al. [10] found that human epididymis protein 4 was more advantageous than CA125.
In addition to these two tumor markers, there are several other markers:
Carcinoembryonic antigen (CEA);
Alpha fetoprotein (AFP);
Carbohydrate antigen 199 (CA199)
Many new tumor markers are still being studied, such as serum macrophage colony-stimulating factor (M-CSF) and lysophosphatidic acid (LPA). The positive rate in serum of LPA ovarian cancer patients was high [11].
Ultrasonography: Ultrasonography is the first choice for ovarian cancer screening to determine the benign and malignant tumors. At present, transvaginal ultrasound, transabdominal ultrasound are widely used.
Laparoscopy: a laparoscope (a thin observation tube with a camera at the end) is inserted into the patient through a small incision in the lower abdomen.
Colonoscopy: If the patient has symptoms of rectal bleeding or constipation, the doctor may ask for a colonoscopy of the large intestine (colon).
CT Scan: CT scan is used to detect ovarian lesions, which can clearly show the location, size and relationship of the tumor to adjacent organs and tissues. It is also used for tumor location, characterization, and staging.
Magnetic Resonance Imaging: MRI provides fine pelvic anatomy , which plays an important role in the detection of ovarian diseases.
Genomics and Proteomics Assays: most of these techniques are currently in the laboratory. In addition, the doctor will also perform a vaginal examination to confirm whether the uterus or ovary is abnormal. It is also necessary to inquire about the patient's history and family history. For women with confirmed ovarian cancer, doctors need to determine the stage and grade.
Treatments for ovarian cancer include surgery, chemotherapy, surgery and chemotherapy, and sometimes radiotherapy. The type of treatment depends on the type, stage and grade of ovarian cancer, as well as the patient's overall health. At present, cytoreductive surgery and platinum-based chemotherapy are the gold standard for the treatment of ovarian cancer.
Surgery for ovarian cancer includes total hysterectomy, bilateral ovariosalpingectomy, tumor reduction, omentectomy [12]. If patients want to preserve their reproductive function, they can have the accessory resection of the affected side, but this also provides more opportunities and risks for the further deterioration of the tumor.
In addition to surgery, chemotherapy is also an important way to treat ovarian cancer patients. Chemotherapy can be used for cancer cells that cannot be removed surgically. At present, paclitaxel combined with platinum drugs is still the first-line chemotherapy drugs for ovarian cancer.
Compared with traditional chemotherapy, targeted therapy has less damage to normal cells and has fewer side effects.
Poly(ADP-ribose) polymerase, PARP inhibitor: Olapani is the most widely used PARP inhibitor. As a PARP inhibitor, olaparib has achieved good tumor inhibition compared with liposomal doxorubicin in phase I clinical trials and randomized trials [13]. A large number of clinical trial data confirmed that it was well tolerated and could significantly prolong the progression-free survival of ovarian cancer patients [14]. PARP inhibitors such as Veliparib, Niraparib and Talazoparib can prolong the progression-free survival of ovarian cancer patients [15].
Angiogenesis Inhibitor: Tumors require blood vessels to meet growth and metastasis requirements, and angiogenesis inhibitors can control tumor growth. Bevacizumab, a monoclonal anti-VEGF antibody, inhibits tumor angiogenesis and slows tumor growth and metastasis by inhibiting the binding of VEGF to its receptors VEGFR1 and VEGFR2.
PI3K/AKT/mTOR Signaling Pathway Inhibitor: PI3K/AKT/mTOR signaling pathway inhibitors can be divided into PI3K inhibitors, mTOR inhibitors, mTOR/PI3K inhibitors, and AKT inhibitors.
Figure 4 Signaling pathways and new therapeutic targets for ovarian cancer [16]
In the targeted therapy of ovarian cancer, the use of antibody drug conjugates (ADCs) greatly increases the specificity of the coupled drug.
3C12 is a monoclonal antibody of Sp17, which is coupled with doxorubicin (DOX) to form an antibody drug conjugate 3C12-DOX. The 3C12-DOX conjugate has obvious tumor suppressing effects in vitro and in vivo, and its safety is superior to that of the chemotherapy drug DOX [17].
The immunotoxin MOC31PE formed by the coupling of EpCAM monoclonal antibody MOC31 and pseudomonas exotoxin A (PE) can inhibit protein synthesis of ovarian cancer cells, weaken cell viability and reduce cancer cell metastasis.
With the deepening of research on ovarian cancer, there will be more ovarian cancer drugs in the future.
References
[1] Gubbels J A, Claussen N, Kapur A K, et al. The detection, treatment, and biology of epithelial ovarian cancer [J]. Journal of Ovarian Research, 2010, 3(1): 8.
[2] Goff B A, Mandel L, Muntz H G, et al. Ovarian carcinoma diagnosis [J]. Cancer, 2015, 89(10): 2068-2075.
[3] Zhang S, Royer R, Li S, et al. Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer [J]. Gynecologic Oncology, 2011, 121(2): 353-357.
[4] Pennington K P, Swisher E M. Hereditary ovarian cancer: Beyond the usual suspects [J]. Gynecologic Oncology, 2012, 124(2): 347-353.
[5] Norquist B M, Harrell M I, Brady M F, et al. Inherited Mutations in Women With Ovarian Carcinoma [J]. Jama Oncol, 2015, 2(4): 482-490.
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[7] Ellen L?kkegaard, Susanne KrügerKjaer, Ellen L?kkegaard. Hormone therapy and ovarian cancer [J]. Lancet, 2015, 386(9998): 298.
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[9] Moss E L, Hollingworth J, Reynolds T M. The role of CA125 in clinical practice [J]. Journal of Clinical Pathology, 2005, 58(3): 308-312.
[10] Ferraro S, Braga F, Lanzoni M, et al. Serum human epididymis protein 4 vs carbohydrate antigen 125 for ovarian cancer diagnosis: a systematic review [J]. Journal of Clinical Pathology, 2013, 66(4): 273-281.
[11] Jacobs I. Discussion: Ovarian Cancer Screening [J]. Gynecologic Oncology, 2003, 88(1-supp-S): 0-0.
[12] King M C. Breast and Ovarian Cancer Risks Due to Inherited Mutations in BRCA1 and BRCA2 [J]. Science, 2003, 302(5645): 643-646.
[13] Kaye S B, Lubinski J, Matulonis U, et al. Phase II, open-label, randomized, multicenter study comparing the efficacy and safety of olaparib, a poly (ADP-ribose) polymerase inhibitor, and pegylated liposomal doxorubicin in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer [J]. Journal of Clinical Oncology, 2012, 30(4): 372-379.
[14] Ledermann J A, El-Khouly F. PARP inhibitors in ovarian cancer: Clinical evidence for informed treatment decisions [J]. British Journal of Cancer, 2015, 113: S10-S16.
[15] Jones P, Wilcoxen K, Rowley M, et al. Niraparib: A Poly (ADP-ribose) Polymerase (PARP) Inhibitor for the Treatment of Tumors with Defective Homologous Recombination [J]. Journal of Medicinal Chemistry, 2015, 58(8): 3302-3314.
[16] Gianpiero D L, Croce C M. The Role of microRNAs in the Tumorigenesis of Ovarian Cancer [J]. Frontiers in Oncology, 2013, 3.
[17] Song J X, Li F Q, Cao W L, et al. Anti-Sp17 monoclonal antibody-doxorubicin conjugates as molecularly targeted chemotherapy for ovarian carcinoma [J]. Targeted Oncology, 2013, 9(3): 263-272.
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