Ovarian Cancer

Overview

Ovarian cancer (OC) remains one of the most deadly cancers affecting women, with an estimated 314,000 new cases diagnosed worldwide annually, making it the eighth most commonly diagnosed cancer. It also accounts for over 207,000 deaths each year, reflecting its high lethality. The disease is often diagnosed at advanced stages (stage III and IV) due to the lack of early symptoms, leading to a poor prognosis.^[1][2] Around 70% of ovarian cancer cases are diagnosed in these late stages, significantly reducing survival rates. The five-year survival rate for ovarian cancer remains dismally low, with an average of 30-45% in most countries.^[3] This poor prognosis is largely attributed to the late detection of the disease and the frequent development of chemoresistance, particularly to platinum-based chemotherapy, the standard treatment for ovarian cancer.^[4] Ovarian cancer is characterized by high heterogeneity, with various histological subtypes and molecular profiles. The most common type, epithelial ovarian cancer (EOC), makes up approximately 90% of all ovarian cancer cases.^[5] Emerging research has shown the critical role of the microbiome in ovarian cancer progression, with recent studies linking both the vaginal and gut microbiota to carcinogenesis. Dysbiosis, or microbial imbalance, in these areas may contribute to inflammation, immune evasion, and tumor progression. The gut microbiome, in particular, is known to influence the immune system and metabolic pathways, potentially playing a significant role in the development of ovarian cancer. Repurposed non-oncology drugs are showing promise in ovarian cancer treatment. These drugs have demonstrated antiproliferative, pro-apoptotic, and antimetastatic properties, offering a more accessible and cost-effective alternative to traditional chemotherapy.

Associated Conditions

Ovarian cancer is closely associated with several gynecological and systemic conditions that increase the risk of developing the disease. One of the most notable associations is with endometriosis, a condition where tissue similar to the uterine lining grows outside the uterus, often on the ovaries. Women with endometriosis face a significantly increased risk of developing ovarian cancer. Studies show that the relative risk of ovarian cancer in women with endometriosis can be as high as 4.2 times compared to the general population. Specifically, women with ovarian endometriosis have a higher likelihood of developing endometrioid and clear cell subtypes of ovarian cancer. Other significant risk factors for ovarian cancer include genetic mutations, particularly in the BRCA1 and BRCA2 genes.^[6] Women carrying mutations in these genes are at a substantially higher risk, with up to 15% of ovarian cancers being attributed to inherited genetic mutations.^[7] These mutations lead to an increased risk of both ovarian and breast cancers, with the lifetime risk of developing ovarian cancer for BRCA1 carriers reaching 40-60%, and for BRCA2 carriers, the risk is about 10-30%.^[8] Obesity and hormonal therapies, including the use of hormone replacement therapy (HRT), are additional risk factors for ovarian cancer. Studies suggest that obesity increases the risk of ovarian cancer due to chronic inflammation and the impact of adiposity on hormonal pathways. Women using HRT, especially after menopause, may experience an elevated risk of developing ovarian cancer due to prolonged exposure to estrogen.

Causes

The causes of ovarian cancer are complex and multifactorial, involving genetic, hormonal, and environmental factors. A major hypothesis for ovarian cancer initiation is hormonal exposure, particularly to estrogen. Extended exposure to estrogen, through factors like early menarche, late menopause, and the use of oral contraceptives or HRT, can increase the risk of ovarian cancer. Ovulation frequency has also been implicated in ovarian cancer development, as frequent ovulation increases the number of times the ovarian surface epithelium is damaged, leading to an accumulation of genetic mutations. Genetic mutations, particularly in BRCA1 and BRCA2, are well-established causes of ovarian cancer.^[9] These genes are involved in DNA repair mechanisms, and mutations in them lead to genomic instability, increasing the risk of cancer development. Lynch syndrome, caused by mutations in MLH1, MSH2, and other mismatch repair genes, is another hereditary condition that predisposes individuals to ovarian cancer.

Emerging theories suggest that microbiome dysbiosis may also play a pivotal role in ovarian cancer pathogenesis. The vaginal and gut microbiota have been shown to influence immune responses and metabolic pathways that can either promote or inhibit cancer development. Dysbiosis in the vaginal microbiota, characterized by a depletion of Lactobacillus and an increase in anaerobic bacteria, has been associated with higher rates of ovarian cancer. Several case–control studies have identified that prior sexually transmitted infection, particularly Chlamydia trachomatis, increases ovarian cancer risk. (The microbiome and gynecologic cancer: cellular mechanisms and clinical applications) This link is still under exploration, but the growing body of evidence suggests that microbiota-related factors may contribute significantly to the disease’s onset and progression.

Causal Theory	Evidence
Hormonal Exposure (Estrogen)	Increased estrogen exposure is linked to higher ovarian cancer risk.
Genetic Mutations (BRCA1/2)	Mutations in BRCA1/2 are linked to a significant increase in ovarian cancer risk.[10]
Microbiome Dysbiosis	Vaginal and gut microbial imbalances contribute to ovarian cancer risk.

Diagnosis

Diagnosing ovarian cancer remains one of the greatest challenges in oncology due to its often silent progression and the lack of effective screening tools. Currently, serum biomarkers like CA125, HE4, and CEA are used in diagnosis, but these markers lack the sensitivity and specificity required for early-stage detection.^[11][12] CA125, for instance, is elevated in only about 50-60% of early-stage cases.^[13][14] Imaging techniques like ultrasound and CT scans are often used to detect masses in the ovaries, but they cannot reliably distinguish between benign and malignant growths. In recent years, liquid biopsy has shown promise as a non-invasive diagnostic method.^[15] Additionally, the role of the microbiome in ovarian cancer diagnosis is being increasingly recognized. Studies have demonstrated that microbiome signatures, particularly from vaginal and gut microbiota, could serve as potential diagnostic biomarkers, offering a new avenue for early detection. This approach may lead to the development of microbiome-based diagnostic tests, allowing for less invasive, earlier detection of ovarian cancer.

Primer

References

1. Reducing Ovarian Cancer Mortality Through Early Detection: Approaches using Circulating Biomarkers.. Trinidad, C. V., Tetlow, A. L., Bantis, L. E., & Godwin, A. K. (2020).. (Cancer Prevention Research (Philadelphia, Pa.), 13(3), 241.)
2. Cellular and molecular processes in ovarian cancer metastasis. A Review in the Theme: Cell and Molecular Processes in Cancer Metastasis.. Yeung, L., Leung, C. S., Yip, P., Au Yeung, C. L., C. Wong, S. T., & Mok, S. C. (2015).. (American Journal of Physiology-Cell Physiology.)
3. Cellular and molecular processes in ovarian cancer metastasis. A Review in the Theme: Cell and Molecular Processes in Cancer Metastasis.. Yeung, L., Leung, C. S., Yip, P., Au Yeung, C. L., C. Wong, S. T., & Mok, S. C. (2015).. (American Journal of Physiology-Cell Physiology.)
4. Reducing Ovarian Cancer Mortality Through Early Detection: Approaches using Circulating Biomarkers.. Trinidad, C. V., Tetlow, A. L., Bantis, L. E., & Godwin, A. K. (2020).. (Cancer Prevention Research (Philadelphia, Pa.), 13(3), 241.)
5. Ovarian cancer in the world: Epidemiology and risk factors.. Momenimovahed, Z., Tiznobaik, A., Taheri, S., & Salehiniya, H. (2019).. (International Journal of Women’s Health, 11, 287.)
6. Ovarian Cancer—Epidemiology, Classification, Pathogenesis, Treatment, and Estrogen Receptors’ Molecular Backgrounds.. Smolarz, B., Biernacka, K., Łukasiewicz, H., Samulak, D., Piekarska, E., Romanowicz, H., & Makowska, M. (2024).. (International Journal of Molecular Sciences, 26(10), 4611.)
7. Ovarian Cancer—Epidemiology, Classification, Pathogenesis, Treatment, and Estrogen Receptors’ Molecular Backgrounds.. Smolarz, B., Biernacka, K., Łukasiewicz, H., Samulak, D., Piekarska, E., Romanowicz, H., & Makowska, M. (2024).. (International Journal of Molecular Sciences, 26(10), 4611.)
8. Ovarian Cancer—Epidemiology, Classification, Pathogenesis, Treatment, and Estrogen Receptors’ Molecular Backgrounds.. Smolarz, B., Biernacka, K., Łukasiewicz, H., Samulak, D., Piekarska, E., Romanowicz, H., & Makowska, M. (2024).. (International Journal of Molecular Sciences, 26(10), 4611.)
9. Ovarian Cancer—Epidemiology, Classification, Pathogenesis, Treatment, and Estrogen Receptors’ Molecular Backgrounds.. Smolarz, B., Biernacka, K., Łukasiewicz, H., Samulak, D., Piekarska, E., Romanowicz, H., & Makowska, M. (2024).. (International Journal of Molecular Sciences, 26(10), 4611.)
10. Ovarian Cancer—Epidemiology, Classification, Pathogenesis, Treatment, and Estrogen Receptors’ Molecular Backgrounds.. Smolarz, B., Biernacka, K., Łukasiewicz, H., Samulak, D., Piekarska, E., Romanowicz, H., & Makowska, M. (2024).. (International Journal of Molecular Sciences, 26(10), 4611.)
11. Reducing Ovarian Cancer Mortality Through Early Detection: Approaches using Circulating Biomarkers.. Trinidad, C. V., Tetlow, A. L., Bantis, L. E., & Godwin, A. K. (2020).. (Cancer Prevention Research (Philadelphia, Pa.), 13(3), 241.)
12. Ovarian Cancer—Epidemiology, Classification, Pathogenesis, Treatment, and Estrogen Receptors’ Molecular Backgrounds.. Smolarz, B., Biernacka, K., Łukasiewicz, H., Samulak, D., Piekarska, E., Romanowicz, H., & Makowska, M. (2024).. (International Journal of Molecular Sciences, 26(10), 4611.)
13. Paradigm Shift: A Comprehensive Review of Ovarian Cancer Management in an Era of Advancements.. Tavares, V., Marques, I. S., Assis, J., Pereira, D., & Medeiros, R. (2024).. (International Journal of Molecular Sciences, 25(3), 1845.)
14. Ovarian cancer: Diagnosis and treatment strategies (Review).. Li, X., Li, Z., Ma, H., Li, X., Zhai, H., Li, X. … Hao, Z. (2024).. (Oncology Letters, 28, 441.)
15. Ovarian cancer: Diagnosis and treatment strategies (Review).. Li, X., Li, Z., Ma, H., Li, X., Zhai, H., Li, X. … Hao, Z. (2024).. (Oncology Letters, 28, 441.)