Ovarian cancer is often fatal because it is usually advanced when diagnosed. The most common histology—high-grade serous epithelial ovarian cancer—is considered as a single clinical entity along with fallopian tube and peritoneal cancers because of shared clinical features. Symptoms are usually absent or nonspecific. Evaluation usually includes ultrasonography, CT or MRI, and measurement of tumor markers (eg, cancer antigen 125). Diagnosis is by histologic analysis. Staging is surgical. Treatment requires hysterectomy, bilateral salpingo-oophorectomy, excision of as much involved tissue as possible (cytoreduction), and usually chemotherapy.
In the United States, ovarian cancer is the second most common gynecologic cancer (affecting approximately 1/70 women). It is the fifth leading cause of cancer-related deaths in women and, in the United States, will cause an estimated 19,710 new cases and 13,270 deaths in 2023 (1). Incidence is higher in high-resource countries.
General reference
1. National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program: Cancer Stat Facts: Ovarian Cancer. Accessed July 14, 2023
Etiology of Ovarian Cancer
Ovarian cancer affects mainly perimenopausal and postmenopausal women. Median age at diagnosis is 63 years (range, 55 to 64 years) (1).
Risk of ovarian cancer is increased by
A history of ovarian cancer in a 1st-degree relative
Nulliparity
Delayed childbearing
Early menarche
Delayed menopause
A personal or family history of endometrial, breast, or colon cancer
Risk is decreased by
Oral contraceptive use
Germline alterations in breast cancer 1 (BRCA1) and breast cancer 2 (BRCA2) genes are identified in 14 to 18% of patients with high-grade serous ovarian cancer; 3% have somatic BRCA mutations (BRCAm) or inactivation due to methylation (2). Deficiency of homologous recombination (which is involved in the repair of DNA damage and replication) is detected in about half of patients with high-grade serous ovarian cancer (3).
Mutations in the autosomal dominant BRCA gene are associated with a 50 to 85% lifetime risk of developing breast cancer. Women with BRCA1 mutations have a 20 to 40% lifetime risk of developing ovarian cancer; risk among women with BRCA2 mutations is 11 to 20%. Incidence of these mutations is higher in people with Ashkenazi Jewish ancestry than in the general population. Mutations in several other genes, including TP53, PTEN, STK11/LKB1, CDH1, CHEK2, ATM, MLH1, and MSH2, have been associated with hereditary breast and/or ovarian cancer.
Germ cell cancers usually occur in women aged < 30. XY gonadal dysgenesis predisposes to ovarian germ cell cancer.
Etiology references
1. National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program: Cancer Stat Facts: Ovarian Cancer. Accessed July 14, 2023
2. Cancer Genome Atlas Research Network: Integrated genomic analyses of ovarian carcinoma. Nature 474 (7353):609–615, 2011. doi: 10.1038/nature10166
3. Li X, Heyer WD: Homologous recombination in DNA repair and DNA damage tolerance. Cell Res 18 (1):99–113, 2008. doi: 10.1038/cr.2008.1
Pathology of Ovarian Cancer
Ovarian cancers are histologically diverse (see table Types of Ovarian Cancer).
Most (90%) ovarian cancers develop from epithelial cells; the rest (germ cell tumors, sex-cord stromal tumors) develop from other ovarian cell types.
Epithelial ovarian carcinoma may be divided into five subtypes:
High-grade serous
Low-grade serous
Endometrioid
Clear cell
Mucinous
High-grade serous ovarian carcinoma is the most common subtype (> 70%) of epithelial carcinomas and usually manifest at an advanced stage. High-grade serous epithelial ovarian, fallopian tube, and peritoneal carcinomas share clinical behavior and treatment. Most high-grade serous carcinomas that manifest as an ovarian mass or as peritoneal disease originate in the fallopian tubes, based on studies of women with BRCA mutations after risk-reducing bilateral salpingo-oophorectomy.
Mucinous ovarian cancers are more likely to manifest at stage I than other histologies and account for nearly 27% of patients with stage I epithelial ovarian cancer.
Types of Ovarian Cancers
Origin | Types |
|---|---|
Epithelium | Brenner tumor Clear cell carcinomas Endometrioid carcinomas Mucinous carcinomas Serous cystadenocarcinomas (most common overall) Transitional cell carcinomas Unclassified carcinomas |
Primary germ cells | Choriocarcinomas Dysgerminomas Embryonal carcinomas Endodermal sinus tumors Immature teratomas Polyembryoma |
Sex cord and stromal cells | Granulosa-theca cell tumors Sertoli-Leydig cell tumors |
Metastases | Breast cancer Cancer of the gastrointestinal tract |
Ovarian cancer spreads by
Direct extension
Exfoliation of cells into the peritoneal cavity (peritoneal seeding)
Lymphatic dissemination to the pelvis and around the aorta
Less often, hematogenously to the liver or lungs
Symptoms and Signs of Ovarian Cancer
Ovarian cancer may be asymptomatic. When symptoms are present, they are nonspecific (eg, dyspepsia, bloating, early satiety, change in bowel habits, urinary frequency). Later, pelvic pain, anemia, cachexia, and abdominal swelling due to ovarian enlargement or ascites usually occur.
An adnexal mass, often solid, irregular, and fixed, may be discovered incidentally. Pelvic and rectovaginal examinations typically detect diffuse nodularity. Few women present with severe abdominal pain secondary to torsion of the ovarian mass.
Germ cell or stromal tumors that produce hormones may have functional effects (eg, hyperthyroidism, feminization, virilization).
Diagnosis of Ovarian Cancer
Ultrasonography (for suspected early cancers) or CT or MRI (for suspected advanced cancers)
Tumor markers (eg, cancer antigen [CA] 125)
Ovarian cancer is suspected in women with the following:
Unexplained adnexal masses
Unexplained abdominal bloating
Changes in bowel habits
Unintended weight loss
Unexplained abdominal pain
An ovarian mass is more likely to be cancer in postmenopausal women. Benign functional cysts can simulate functional germ cell or stromal tumors in reproductive-age women.
A pelvic mass plus ascites usually indicates ovarian cancer but sometimes indicates Meigs syndrome (a benign fibroma with ascites and right hydrothorax).
Imaging
If early cancer is suspected, ultrasonography is done first; the following findings suggest cancer:
A solid component
Surface excrescences
Size > 6 cm
Irregular shape
Low vascular resistance detected by transvaginal Doppler flow studies
If advanced cancer is suspected (eg, based on ascites, abdominal distention, or nodularity or fixation detected during physical examination), CT or MRI is usually done before surgery to determine extent of the cancer.
Tumor markers
A mixed solid and cystic pelvic mass in postmenopausal women, especially if CA 125 is elevated, raises suspicion of ovarian cancer.
Histology
A biopsy is not routinely recommended unless a patient is not a surgical candidate, because it may cause leakage of cells and upstaging of the cancer. Rarely, when biopsy is done, samples are obtained by needle biopsy for masses or by needle aspiration for ascitic fluid.
For masses that appear benign on ultrasonography, ultrasonography is repeated after 6 weeks and then every 3 to 6 months until it confirms that no malignant features are developing. Such benign-appearing masses include benign cystic teratomas (dermoid cysts), follicular cysts, and endometriomas. Masses that are indeterminate may require exploratory surgery and unilateral salpingo-oophorectomy to confirm histology.
Staging
Ovarian cancer is staged surgically (see table FIGO Surgical Staging of Ovarian, Fallopian Tube, and Peritoneal Cancer).
FIGO Surgical Staging of Ovarian, Fallopian Tube, and Peritoneal Cancer
Stage | Description |
|---|---|
I | Tumor limited to the ovaries or fallopian tubes |
| Tumor limited to one ovary (capsule intact) or fallopian tube; no tumor on ovarian or fallopian tube surface; no malignant cells in ascitic fluid or in peritoneal washings |
| Tumor limited to one or both ovaries (capsule intact) or fallopian tubes; no tumor on the surface of ovary or fallopian tube; no malignant cells in ascitic fluid or in peritoneal washings |
| Tumor limited to one or both ovaries or fallopian tubes, plus any of the following: |
|
|
|
|
|
|
II | Tumor involving one or both ovaries or fallopian tubes with pelvic extension (below pelvic brim) or peritoneal cancer |
| Extension and/or implants on the uterus, fallopian tubes, and/or ovaries |
| Extension and/or implants on other pelvic intraperitoneal tissues |
III | Tumor involving one or both ovaries or fallopian tubes or peritoneal cancer with microscopically confirmed peritoneal metastases outside the pelvis and/or metastasis to the retroperitoneal lymph nodes |
| Positive retroperitoneal lymph nodes only (histologically proved) |
| Metastasis ≤ 10 mm in largest dimension |
| Metastasis > 10 mm in largest dimension |
| Microscopic extrapelvic (beyond the pelvic brim) peritoneal involvement, with or without positive retroperitoneal lymph nodes |
| Macroscopic peritoneal metastases that extend beyond the pelvis and that are ≤ 2 cm in largest dimension, with or without positive retroperitoneal lymph nodes |
IIIC | Macroscopic peritoneal metastases that extend beyond the pelvis and are > 2 cm in largest dimension, with or without metastasis to retroperitoneal lymph nodes (includes extension of tumor to the capsule of the liver and spleen without parenchymal involvement of either organ) |
IV | Distant metastases excluding peritoneal metastases |
| Pleural effusion with positive cytology |
| Parenchymal metastasis and/or metastases to extra-abdominal organs (including inguinal lymph nodes and lymph nodes outside the abdominal cavity) |
Adapted from staging established by the International Federation of Gynecology and Obstetrics (FIGO): Berek JS, Renz M, Kehoe S,et al: Cancer of the ovary, fallopian tube, and peritoneum: 2021 update. Int J Gynaecol Obstet 155 Suppl 1:61–85, 2021. doi: 10.1002/ijgo.13878 | |
If early-stage cancer is suspected, staging may be done by laparoscopy or robotic-assisted laparoscopic surgery. Otherwise, an abdominal midline incision that allows adequate access to the upper abdomen is required.
The staging procedure includes hysterectomy and bilateral salpingo-oophorectomy. All peritoneal surfaces, hemidiaphragms, and abdominal and pelvic viscera are inspected and palpated. Washings from the pelvis, abdominal gutters, and diaphragmatic recesses are obtained, and multiple biopsies of the peritoneum in the central and lateral pelvis and in the abdomen are done. For early-stage cancer, the infracolic omentum is removed, and pelvic and para-aortic lymph nodes are sampled. Sentinel lymph node biopsy is not routinely done in patients with ovarian cancer.
Cancers are also graded histologically, and epithelial ovarian cancers are classified as low-grade (grade 1) or high-grade (grade 2 or 3).
Treatment of Ovarian Cancer
Usually hysterectomy and bilateral salpingo-oophorectomy
Cytoreductive surgery
(See also National Comprehensive Cancer Network (NCCN): NCCN Clinical Practice Guidelines in Oncology: Ovarian Cancer.)
Treatment of ovarian, fallopian tube, and peritoneal cancer is based on stage, grade, and histology:
For stage IA or IB ovarian tumors (confined to the ovary) and/or grade 1 endometrioid tumors, prognosis is excellent (survival 90%) after surgery alone.
For stage III or IV, primary surgical cytoreduction followed by systemic chemotherapy is the standard treatment. Neoadjuvant chemotherapy followed by cytoreductive surgery is the preferred option for patients who are not candidates for surgical resection (due to location and volume of the cancer or because of comorbidities).
Hysterectomy and bilateral salpingo-oophorectomy are usually indicated, but fertility preservation by conserving the unaffected ovary and uterus may be considered for stage I nonepithelial or low-grade unilateral epithelial ovarian cancers in young patients.
Potential indications for neoadjuvant chemotherapy include one or more of the following:
Multiple liver metastases
Lymphadenopathy in the porta hepatis
Suprarenal para-aortic lymph nodes
Diffuse mesenteric disease
Evidence of pleural or parenchymal lung disease
In a large randomized trial, neoadjuvant chemotherapy followed by surgery had less perioperative morbidity than primary surgery followed by chemotherapy and similar long-term survival rates (1).
Surgical staging and cytoreduction
The surgical procedure for ovarian, fallopian tube, and peritoneal cancers includes staging and cytoreduction (all visibly involved tissue is surgically removed if possible). Cytoreduction is associated with increased survival time; the volume of residual disease remaining after cytoreduction correlates inversely with survival time.
Cytoreductive surgery for ovarian cancer usually includes
Supracolic omentectomy, sometimes with rectosigmoid resection (usually with primary reanastomosis)
Radical peritoneal stripping
Resection of diaphragmatic peritoneum or splenectomy
Cytoreduction may be
Complete: Cytoreduction to no grossly visible disease
Optimal: Cytoreduction with residual disease that is ≤ 1 cm in maximum tumor diameter, as defined by the Gynecologic Oncology Group
Suboptimal: Cytoreduction with any visible tumor nodules > 1 cm remaining
Because cytoreduction is associated with increased survival, being able to predict when cytoreduction to no gross residual disease can be done is important, but doing so is difficult; there are no uniform criteria.
Optimal cytoreduction is less likely if patients have the following:
Poor performance status
Age > 60 years
American Society of Anesthesiologists physical status 3 or 4
Medical comorbidities
Poor nutritional status
Extra-abdominal disease
Large tumor bulk
Involvement of large bowel
Metastases to retroperitoneal lymph nodes above the renal vessels and > 1 cm in largest dimension
Parenchymal liver involvement
A preoperative CA 125 > 500 U/mL
The Fagotti score, based on seven laparoscopic findings, can help predict the likelihood of optimal cytoreduction in patients with advanced ovarian cancer. This scoring system assigns a value of 0 or 2 depending on whether disease is present in certain locations. If patients score ≥ 10, optimal cytoreduction is very unlikely. If they score < 10, they are considered candidates for cytoreductive surgery (2).
Diagnostic laparoscopy before laparotomy can spare patients an unnecessary laparotomy, which would result in suboptimal cytoreduction. Laparoscopy enables clinicians to do a tissue biopsy, make a definitive diagnosis, and analyze the biopsy sample. Thus, patients who are not candidates for cytoreduction can begin chemotherapy treatment earlier. Laparoscopic findings indicating that optimal cytoreduction is unlikely include
Omental cake
Extensive peritoneal or diaphragmatic carcinomatosis
Mesenteric retraction
Bowel and stomach infiltration
Spleen and/or liver superficial metastasis
Systemic or intraperitoneal chemotherapy
In most patients with newly diagnosed ovarian cancer, the disease has spread widely throughout the peritoneum; thus, treatment involves one of the following (see table Postoperative Treatment of Ovarian Cancer by Stage and Type):
Staging and cytoreduction, followed by 6 cycles of IV chemotherapy
3 cycles of neoadjuvant chemotherapy, followed by surgery and 3 more chemotherapy cycles
For certain patients at higher risk of recurrence (eg, those who have pleural effusions or ascites and do not have a BRCA
3).
PARP (polyadenosine diphosphate-ribose polymerase) enzymes are essential to the repair of single-strand breaks in DNA. Inhibition of PARP enzymes leads to persistent single-strand breaks, which cause double-strand breaks to accumulate during DNA replication and ultimately lead to tumor cell death.
In several clinical trials, a PARP inhibitor (PARPi) after chemotherapy improved progression-free survival in women who have serous or high-grade endometrioid ovarian cancer and who completed first-line chemotherapy, even if they did not have a BRCA1 or BRCA2 mutation (4, 5, 6, 7).
BRCABRCA mutation (9).
The VELIA trial included patients with previously untreated stage III or IV high-grade serous ovarian carcinoma. This three-arm trial compared standard chemotherapy alone versus standard chemotherapy plus veliparib versus standard chemotherapy plus veliparib followed by maintenance therapy with veliparib (4). Progression-free survival was longest with veliparib chemotherapy plus veliparib maintenance therapy.
Intraperitoneal chemotherapy using a catheter has been suggested as an alternative to IV chemotherapy. Intraperitoneal chemotherapy delivers the agents directly to the peritoneal surface and thus eliminates residual microscopic disease. In advanced-stage ovarian cancer, combination treatment with IV and intraperitoneal chemotherapy appears to prolong overall survival after primary cytoreductive surgery (10). This approach is not without complications; catheter-related complications can limit its use (11).
Direct delivery of chemotherapy to the abdominal cavity under hyperthermic conditions (HIPEC) intraoperatively after cytoreduction has been used in patients with colon cancer and is under study for ovarian cancer. The potential benefit of HIPEC is increased sensitivity to chemotherapy by impairing DNA repair, it induces apoptosis and activates heat-shock proteins.
Postoperative Treatment of Ovarian Cancer by Stage and Type
Stage and Type | Treatment* |
|---|---|
Stage IA or B/grade 1 epithelial adenocarcinoma | No postoperative therapy |
Stage IA or B/grade 2 or 3 cancers Stage II cancer | |
Stage III cancer | 6 courses of chemotherapy† as for stage IA or B/grade 2 or 3 |
Stage IV cancer | Infrequently, radiation therapy |
Germ cell tumors Stage II or III stromal tumors | |
BRCA mutations or homologous recombination deficiency. | |
PARP = polyadenosine diphosphate-ribose polymerase. | |
Even if chemotherapy results in a complete clinical response (ie, normal physical examination, normal serum CA 125, negative CT scan of the abdomen and pelvis), approximately 50% of patients with stage III or IV cancer have residual tumor. Of patients with persistent elevation of CA 125, 90 to 95% have residual tumor.
Recurrent disease
Recurrence of ovarian cancer can be detected serologically with tumor markers (eg, CA 125) and/or by radiologic signs of progression. Treatment of recurrence depends on the time between the completion of platinum-based treatment and detection of recurrence (platinum-free interval [PFI]):
A PFI of ≥ 6 months suggests platinum-sensitive disease.
A PFI of < 6 months suggests platinum-resistant disease.
12). Targeted therapy with biologic agents is under study.
For patients with recurrent high-grade serous or endometrioid ovarian cancer with platinum-sensitive tumors and who had a BRCA1 or BRCA215).
Randomized trials of secondary cytoreductive surgery in patients with platinum-sensitive ovarian cancer have had variable results. Several trials compared surgical cytoreduction followed by chemotherapy versus chemotherapy alone, In one trial (GOG-0213), overall survival time did not increase, but in other trials, there were significant increases in overall survival time (in DESKTOP III, 53.7 versus 46.0 months) or progression-free survival time (in SOC-1, 17.4 versus 11.9 months [16, 17, 18]).
Treatment references
1. Vergote I, Tropé CG, Amant F, et al; Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N Engl J Med 2010;363 (10):943–953, 2010. doi:10.1056/ NEJMoa0908806
2. Petrillo M, Vizzielli G, Fanfani F, et al: Definition of a dynamic laparoscopic model for the prediction of incomplete cytoreduction in advanced epithelial ovarian cancer: Proof of a concept. Gynecol Oncol 139 (1):5–9, 2015. doi:10.1016/j.ygyno.2015.07.095 Epub 2015 Jul 18.
3. Pfisterer J, Joly F, Kristensen G, et alJ Clin Oncol 41(4):893-902, 2023. doi:10.1200/JCO.22.01010
4. Coleman RL, Fleming GF, Brady MF, et al: Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer. N Engl J Med 381 (25):2403–2415, 2019. doi: 10.1056/NEJMoa1909707 Epub 2019 Sep 28.
5. González-Martín A, Pothuri B, Vergote I, et al: Niraparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med 381 (25):2391–2402, 2019. doi: 10.1056/NEJMoa1910962 Epub 2019 Sep 28.
6. Ray-Coquard I, Pautier P, Pignata S, et al: Olaparib plus bevacizumab as first-line maintenance in ovarian cancer. N Engl J Med 381 (25):2416–2428, 2019. doi: 10.1056/NEJMoa1911361
7. Moore K, Colombo N, Scambia G, et al: Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med 379 (26):2495–2505, 2018. doi: 10.1056/NEJMoa1810858 Epub 2018 Oct 21.
8. Banerjee S, Moore KN, Colombo N, et al: Maintenance olaparib for patients with newly diagnosed advanced ovarian cancer and a BRCA mutation (SOLO1/GOG 3004): 5-year follow-up of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 22 (12):1721–1731, 2021. doi: 10.1016/S1470-2045(21)00531-3 Epub 2021 Oct 26
9. Ray-Coquard I, Pautier P, Pignata S, et al: Olaparib plus Bevacizumab as First-Line Maintenance in Ovarian Cancer. N Engl J Med 381(25):2416-2428, 2019. doi:10.1056/NEJMoa1911361
10. Armstrong DK, Bundy B, Wenzel L, et al: Intraperitoneal cisplatin and paclitaxelin in ovarian cancer. N Engl J Med 354:34–43, 2006. doi: 10.1056/NEJMoa052985
11. Wright AA, Cronin A, Milne DE, et al: Use and effectiveness of intraperitoneal chemotherapy for treatment of ovarian cancer. J Clin Oncol 33:2841–2847, 2015. doi: 10.1200/JCO.2015.61.4776
12. Zsiros E, Lynam S, Attwood KM, et al: Efficacy and safety of pembrolizumab in combination with bevacizumab and oral metronomic cyclophosphamide in the treatment of recurrent ovarian cancer: A phase 2 nonrandomized clinical trial. JAMA Oncol 7 (1):78–85, 2021. doi: 10.1001/jamaoncol.2020.5945
13. Ledermann J, Harter P, Gourley C, et al: Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med 366 (15):1382–1392, 2012. doi: 10.1056/NEJMoa1105535 Epub 2012 Mar 27.
14. Pujade-Lauraine E, Ledermann JA, Selle F, et al: Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): A double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol 18 (9):1274–1284, 2017. doi: 10.1016/S1470-2045(17)30469-2 Epub 2017 Jul 25.
15. Poveda A, Floquet A, Ledermann JA, et al: Olaparib tablets as maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a final analysis of a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol 22(5):620-631, 2021. doi:10.1016/S1470-2045(21)00073-5
16. Coleman RL, Spirtos NM, Enserro D, et al: Secondary surgical cytoreduction for recurrent ovarian cancer. N Engl J Med 381 (20):1929–1939, 2019. doi: 10.1056/NEJMoa1902626
17. Harter P, Sehouli J, Vergote I, et al: Randomized trial of cytoreductive surgery for relapsed ovarian cancer. N Engl J Med 385 (23):2123–2131, 2021. doi: 10.1056/NEJMoa2103294
18. Shi T, Zhu J, Feng Y, et al: Secondary cytoreduction followed by chemotherapy versus chemotherapy alone in platinum-sensitive relapsed ovarian cancer (SOC-1): A multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 22 (4):439–449, 2021. doi: 10.1016/S1470-2045(21)00006-1 Epub 2021 Mar 8.
Prognosis for Ovarian Cancer
In women with ovarian cancer, the 5-year survival rates with treatment are (1)
Stage I: 85 to 95%
Stage II: 70 to 78%
Stage III: 40 to 60%
Stage IV: 15 to 20%
Prognosis is worse when tumor grade is higher or when surgery cannot remove all visibly involved tissue; in such cases, prognosis is best when the involved tissue can be reduced to < 1 cm in diameter or ideally to a microscopic residual amount (cytoreductive surgery).
With stage III or IV ovarian cancer, recurrence rate is approximately 70% (2).
Prognosis references
1. National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program: Cancer Stat Facts: Ovarian Cancer. Accessed August 31, 2023
2. Kurnit KC, Fleming GF, Lengyel E: Updates and new options in advanced epithelial ovarian cancer treatment. Obstet Gynecol 137(1):108-121, 2021. doi:10.1097/AOG.0000000000004173
Prevention of Ovarian Cancer
Estrogen-progestin contraceptive use is associated with a decreased risk of ovarian cancer; in average-risk patients, risk is decreased by approximately 50% after 5 years of use and 80% after ≥ 10 years of use (1).
Patients with BRCA1 or BRCA2 gene mutations should be referred to a gynecologic oncologist for counseling regarding ovarian cancer risk reduction. For these patients, risk-reducing bilateral salpingo-oophorectomy decreases the risks of ovarian and, to a lesser degree, breast cancer (2, 3). Use of estrogen-progestin contraceptives is not recommended as an alternative method of ovarian cancer prevention, except for patients who are not candidates for surgery or choose not to undergo surgery.
For patients with BRCA mutations, use of oral contraceptives has been found to be associated with a reduction in ovarian cancer risk; however, other formulations as vaginal ring, intrauterine device, or patches have not been studied, and it is unknown whether they provide similar ovarian cancer prevention. A meta-analysis including 1503 cases of ovarian cancer in women with BRCA1 or BRCA2 mutations showed a 50% reduction in ovarian cancer risk associated with oral contraceptives (4); there was no significant increase in breast cancer risk with use of current oral contraceptive formulations. A large study included in the meta-analysis (n=798 women with ovarian cancer) reported a 5% decrease in the risk of ovarian cancer per year of oral contraceptive use (5). A large cohort study found a maximum benefit when used for 3 to 5 years (6).
Screening
There is no screening test for ovarian cancer. However, women with a known hereditary risk, such as those with BRCA mutations, should be followed closely.
A meta-analysis of 51 studies found that CA 125 has a sensitivity of 79% and a specificity of 78% (7); thus, CA 125 is not recommended as a screening test for asymptomatic, average-risk women.
Multimodal screening has been studied but has not been determined to be effective. A large randomized trial compared annual multimodal screening (CA 125, transvaginal ultrasonography [TVUS]) with no screening. At a median follow-up of 16.3 years, multimodal screening detected more women with early stage ovarian or fallopian tube cancer; however, there was no significant reduction in deaths due to ovarian or fallopian tube cancer (8).
Most breast and ovarian cancers are sporadic, rather than caused by a known gene mutation; only approximately 15% of ovarian cancer cases are caused by BRCA mutations (9). However, evaluation for a hereditary cancer syndrome should be considered in all women diagnosed with ovarian, fallopian tube, or peritoneal cancer, and they should have a genetic risk evaluation. A germline or somatic BRCA1 or BRCA2 mutation may affect treatment and maintenance therapy. A detailed personal and family history of other cancers should be obtained to identify women who are more likely to have a hereditary cancer syndrome (eg, one involving BRCA1 or BRCA2 mutations, Lynch syndrome [hereditary nonpolyposis colorectal cancer]).
Women should be screened for abnormalities in the BRCA gene if their family history includes any of the following:
Diagnosis of ovarian cancer in a 1st-degree relative before age 40
Diagnosis of breast and ovarian cancer in only one 1st-degree relative if one of the cancers was diagnosed before age 50
Two cases of ovarian cancer among 1st- and 2nd-degree relatives of the same lineage
Two cases of breast cancer and one case of ovarian cancer among 1st- or 2nd-degree relatives of the same lineage
One case of breast and one case of ovarian cancer among 1st- or 2nd-degree relatives of the same lineage if breast cancer was diagnosed before age 40 or if ovarian cancer was diagnosed before age 50
Two cases of breast cancer among 1st- or 2nd-degree relatives of the same lineage if both cases were diagnosed before age 50
Two cases of breast cancer among 1st- or 2nd-degree relatives of the same lineage if one was diagnosed before age 40
Also, if Ashkenazi Jewish women have one family member with breast cancer diagnosed before age 50 or with ovarian cancer, screening for abnormalities in the BRCA gene should be considered.
Prevention references
1. Iversen L, Sivasubramaniam S, Lee AJ, Fielding S, Hannaford PC: Lifetime cancer risk and combined oral contraceptives: the Royal College of General Practitioners' Oral Contraception Study. Am J Obstet Gynecol 216(6):580.e1-580.e9, 2017. doi:10.1016/j.ajog.2017.02.002
2. Marchetti C, De Felice F, Palaia I, et al: Risk-reducing salpingo-oophorectomy: a meta-analysis on impact on ovarian cancer risk and all cause mortality in BRCA 1 and BRCA 2 mutation carriers. BMC Womens Health 14:150, 2014. Published 2014 Dec 12. doi:10.1186/s12905-014-0150-5
3. Choi YH, Terry MB, Daly MB, et al: Association of risk-reducing salpingo-oophorectomy with breast cancer risk in women with BRCA1 and BRCA2 pathogenic ariants. JAMA Oncol 7(4):585-592, 2021. doi:10.1001/jamaoncol.2020.7995
4. Iodice S, Barile M, Rotmensz N, et al: Oral contraceptive use and breast or ovarian cancer risk in BRCA1/2 carriers: a meta-analysis. Eur J Cancer 46(12):2275-2284, 2010. doi:10.1016/j.ejca.2010.04.018
5. McLaughlin JR, Risch HA, Lubinski J, et al: Reproductive risk factors for ovarian cancer in carriers of BRCA1 or BRCA2 mutations: a case-control study. Lancet Oncol 8(1):26-34, 2007. doi:10.1016/S1470-2045(06)70983-4
6. Kotsopoulos J, Lubinski J, Gronwald J, et al: Factors influencing ovulation and the risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers. Int J Cancer 137(5):1136-1146, 2015. doi:10.1002/ijc.29386
7. Dodge JE, Covens AL, Lacchetti C, et al: Preoperative identification of a suspicious adnexal mass: a systematic review and meta-analysis. Gynecol Oncol 126(1):157-166, 2012. doi:10.1016/j.ygyno.2012.03.048
8. Menon U, Gentry-Maharaj A, Burnell M, et al : Ovarian cancer population screening and mortality after long-term follow-up in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): A randomised controlled trial. Lancet 397 (10290):2182–2193, 2021. doi: 10.1016/S0140-6736(21)00731-5
9. Zhang S, Royer R, Li S, et al: Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer. Gynecol Oncol 121(2):353-357, 2011. doi:10.1016/j.ygyno.2011.01.020
Key Points
Ovarian cancer affects mostly postmenopausal and perimenopausal women; nulliparity, delayed childbearing, early menarche, delayed menopause, and certain genetic markers (BRCA mutations) increase risk.
Symptoms (eg, dyspepsia, bloating, early satiety, gas pains, backache) are nonspecific.
If cancer is suspected, do ultrasonography first (sometimes followed by CT or MRI) and measure tumor markers (eg, CA 125).
Effective screening is not available for average-risk women; screen women at high risk (eg, BRCA mutation carriers) with ultrasonography and/or CA 125.
More Information
The following English-language resource may be useful. Please note that THE MANUAL is not responsible for the content of this resource.
National Cancer Institute: Ovarian, Fallopian Tube, and Primary Peritoneal Cancer: This web site provides links to information about causes, genetics, prevention, and treatment of ovarian, fallopian tube, and primary peritoneal cancer, as well as links to information about screening, statistics, and supportive and palliative care.
