Comprehensive Ovarian Cancer Treatment and Management

What is Ovarian Cancer?

With an estimated 313 959 new cancer cases and 207 252 deaths in women, ovarian cancer is the 7^th most commonly diagnosed cancer and the 8^th cause of cancer death in women in 2020, representing approximately 6.6% of diagnosed cancers and 4.4% of deaths in women1.

By 2040, the number of women around the world diagnosed with ovarian cancer will rise almost 42% and the number of women dying from ovarian cancer each year is projected to increase to over 50% from 20202.

Because of its anatomical location, ovarian cancer is asymptomatic and is frequently detected in its advanced stages. Two-thirds of women are currently diagnosed with late-stage disease, when the cancer has already spread beyond the ovaries, making it harder to treat, and greatly reducing survival.

There are different types of ovarian cancer tumors, which are named after the type of cell they come from, the three main cell types that make up the ovary. They are:

– Epithelial ovarian cancer is the most common type of ovarian cancer. Primary peritoneal cancer and fallopian tube cancer are similar to epithelial ovarian cancer and are treated in the same way.

– Germ cell ovarian tumors are rare and usually affect girls and young women up to their early 30s. Ovarian teratoma is the most common type.

– Sex cord-stromal ovarian tumors can be non-cancerous (benign) or cancerous (malignant). Granulosa cell tumors are the most common type.

– Borderline ovarian tumors are abnormal cells that form in the tissue covering the ovary. They are not cancer and are usually cured with surgery.

(Figure 1).

Figure 1 : Different types of ovarian cancer tumors

Epithelial ovarian cancer (EOC) or ovarian carcinoma accounts for a majority (85%-90%) of all ovarian cancers. It is generally thought of as one of three types of cancer that include ovarian, fallopian tube and primary peritoneal (lining tissues of the pelvis and abdomen) cancer. All three tumor types behave and are treated the same way.

The four most common tumor cell types of epithelial ovarian cancer are serous, mucinous, clear cell, and endometrioid, with serous epithelial ovarian cancer being the most common type, accounting for more than 50% of epithelial carcinomas. Most serous ovarian cancers are high-grade (aggressively growing) tumors.

Biomarker testing in ovarian cancer treatment

Ovarian cancer is a diverse disease with more than 30 types of ovarian cancers. Biomarker testing helps identify which biomarkers (including genetic mutations, which are gene changes) the patient might have in order to determine their ovarian cancer subtype3. This can be a critical part of understanding each patient’s ovarian cancer, particularly as knowing the subtype has the potential to help the patient and healthcare professional team make informed decisions about the patient’s care. The best mode of treatment will depend on the ovarian cancer subtype but can include chemotherapy, radiation, surgery, targeted therapies, or a combined approach4. By tailoring treatments based on a comprehensive understanding of the cancer, we can improve the chances of successful outcomes.

What type of biomarkers are used to determine the best treatment option for ovarian cancer patients?

The advent of precision medicine with somatic tumor testing and genomic sequencing has helped elucidate the molecular pathogenesis of ovarian cancers⁵. However, the molecular pathogenesis of rare ovarian malignancies is less well defined. Some have associated pathognomonic genomic alterations. Nearly all adult type granulosa cell tumors contain a missense mutation of the FOXL2 gene, which encodes a transcription factor essential for granulosa cells⁶.

Approximately 60% of sertoli-leydig cell tumors possess DICER1 mutations⁶. These biomarkers can help the pathologist to make a final diagnosis and influence the patient’s treatment plan.

Actionable biomarkers are defined as genetic alterations that are functional in driving malignancy and may be targeted by an approved treatment (Table 1). They can lead to oncogenic activation through several mechanisms, including point mutations insertions/deletions and rearrangements7. Broadly, actionable mutations guiding targeted therapies can be classified according to gene rearrangements (e.g. NTRK, RET) or variants including point mutations, insertions/deletions (e.g. BRCA1/2 and BRAF) and genomic signatures (HRD). These actionable biomarkers help determine whether a targeted therapy might be appropriate.

Genomic signatures such as TMB and MSI or PDL-1 expression level can be used to determine whether an immunotherapy drug might be appropriate.

Table 1: Biomarkers with current FDA or EMA approved treatment for Ovarian Cancer (As of June 2023)

Genes	Biomarkers types	Atlerations	FDA-approved therapy	EMA-approved therapy
BRCA1/2	Loss of function mutation	NA	Niraparib, Olaparib, Rucaparib Olaparib + Bevacizumab	Olaparib Olaparib + Bevacizumab
BRAF	Activating mutation	V600E	Dabrafenib + Trametinib	Dabrafenib + Trametinib
RET	Rearrangements	NA	Selpercatinib	Selpercatinib
NTRK	Gene fusion	NA	Larotrectinib, Entrectinib	Larotrectinib, Entrectinib
HRD	Genomic signature	Positive	Olaparib, Niraparib Olaparib + Bevacizumab	Olaparib Olaparib + Bevacizumab
MSI	Genomic signature	Unstable	Pembrolizumab	Pembrolizumab
TMB	Genomic signature	High	Pembrolizumab	None

HRD stands for Homologous Recombination Deficiency, a lack of functional components in one or more of the DNA repair pathways and a common trait of cancer cells, which have a high genetic mutation rate.

How can OncoDEEP^® test help oncologists with ovarian cancer treatment plan?

Genetic testing allows both clinicians and patients to make an informed decision when it comes to the treatment they receive. Conducting testing prior to or at the point of diagnosis can be important in improving patient care and enabling access to certain targeted therapies7. By understanding the heritability of a woman’s cancer (if the mutation she possesses can be inherited) a patient’s family can also understand their risk of developing the disease – understanding the full picture has important implications for cancer risk assessment and prevention among relatives8.

Our OncoDEEP^® test is designed to detect all the biomarkers as mentioned in Table 1 (and more!). We understand the challenges in detecting large array of biomarkers from low quantity and poor-quality tumor genetic material; hence with a team of experts, we have developed, optimized and validated OncoDEEP^® test to be able to detect low level of biomarker in difficult to analyse tumor biopsy. Our test is sensitive enough to detect allelic frequency of 5%, and even down to 1% for FDA and EMA-approved biomarkers!! Upon detecting any of the biomarkers that are associated with treatment options or recruiting clinical trials, a report will be generated to help oncologists work out the most suitable cancer treatment plan for their patients.

1. World Health Organization. Globocan 2020 Fact Sheet. Available at: https://gco.iarc.fr/today/data/factsheets/populations/900-world-fact-sheets.pdf. Accessed September 2021.

2. https://worldovariancancercoalition.org/about-ovarian-cancer/key-stats/

3. Oncology Pro. BRCA1 and BRCA2 In Ovarian Cancer: ESMO Biomarker Factsheet. Available at: https://oncologypro.esmo.org/education-library/factsheets-on-biomarkers/brca1-and-brca2-in-ovarian-cancer.

4. ESMO. ESMO patient guide series -Ovarian cancer (2017). Available at https://www.esmo.org/content/download/10097/201883/1/EN-Ovarian-Cancer-Guide-for-Patients.pdf.

5. Radu, M.R.; Pradatu, A.; Duica, F.; Micu, R.; Cretoiu, S.M.; Suciu, N.; Cretoiu, D.; Varlas, V.N.; Radoi, V.E. Ovarian Cancer: Biomarkers and Targeted Therapy. Biomedicines 2021, 9, 693.

6. Barakat, R.R.; Markman, M.; Randall, M. (Eds.) Principles and Practice of Gynecologic Oncology; Lippincott Williams & Wilkins: Philadelphia, PA, USA, 2017.

7. Ngoi NYL, et al. The role of homologous recombination deficiency testing in ovarian cancer and its clinical implications: do we need it? ESMO Open Cancer Horizons 2021;6(3):1-12.

8. National Cancer Institute. (2019). BRCA1 and BRCA 1: Cancer Risk and Genetic Testing. Available at http://www.cancer.gov/about-cancer/causes-prevention/genetics/brca-fact-sheet. Accessed May 2022.

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