Hope for ovarian cancer screening test

 

Most cancers can be cured by surgery in their early stages, when the tumors are localized. Once they have metastasized, surgery alone is not successful, and chemotherapy has not had high success in the case of ovarian cancers. What makes ovarian cancer so deadly is that distinct symptoms seldom develop until the cancer spreads outside the ovaries. The major goal for screening, therefore, is to detect ovarian cancer before it metastasizes. Currently less than 20% of cases are diagnosed before the cancer spreads.

Researchers at Johns Hopkins have developed a new “liquid biopsy” test that they hope will eventually have the capacity to identify the presence of relatively early cancers. In an early assessment, this test detected 98% of ovarian cancers in a test group of patients who had stage II or greater disease that had not yet metastasized.[1] From this success, the Johns Hopkins researchers hope to improve the test so it can be a screening tool to detect the disease in earlier stages.

Because ovarian cancer is typically diagnosed in its later stages, generally during an evaluation of someone who is symptomatic, it is the leading cause (53%) of gynecologic cancer deaths in the United States. This ‘silent cancer’ is often accompanied by nonspecific symptoms, sometimes described as similar to common conditions such as irritable bowel syndrome: pelvic pain, abdominal discomfort and distention, bloating after meals, feeling full quickly, constipation, nausea. Sometimes women complain of urinary frequency or, rarely, irregular vaginal bleeding. In advanced stages, ovarian cancer is often accompanied by fatigue, nonspecific gastrointestinal symptoms, or shortness of breath due to pleural effusion.[2]

Having an effective screening test for earlier detection would be life-saving. Currently, clinicians have three modalities to screen for the early stages of ovarian cancer in asymptomatic women: periodic bimanual pelvic examination, serum CA-125 measurement, and transvaginal ultrasound. The U.S. Preventive Services Task Force (USPSTF) recommends against routine screening with any of these modalities (D Statement), because the potential harms from false-positive results outweigh the potential benefits.[3] In fact, a recent large randomized controlled trial of simultaneous screening with CA-125 and transvaginal ultrasound, compared with the usual care, did not reduce deaths from ovarian cancer. ^[4] At the same time, the simultaneous screening produced false-positive results that led to complications during diagnostic evaluation.

Guidelines from the U.S. National Institutes of Health (NIH), however, suggest that the currently available screening tests should be offered annually to women who have familial risk factors for ovarian cancer.[5] The risk of ovarian cancer is 5% if one first-degree relative had ovarian cancer and 7% if two or more first-degree relatives had the condition. Women with BRCA mutations are at greater risk of ovarian cancer, about 35% to 70% for BRCA-1 and 10% to-30% for BRCA-2 by age 70.⁵ There is no accurate method to detect early ovarian cancer in these high-risk patients.

Hoping to improve the options for screening, researchers developed the new liquid biopsy test, called CancerSEEK. In a case-control study, the test was used to detect 8 types of cancer, including ovarian cancer and four other cancers for which there are no screening tests available for average-risk individuals. Recruited into the study were 812 health controls with no history of cancer and 1,005 patients with cancers in the ovary, liver, stomach, pancreas, esophagus, colon, lung, or breast that had not yet spread to other tissues. None of the patients had begun chemotherapy. Overall, the CancerSEEK test detected 70% of the cancers; for ovarian cancer alone, the test was highly sensitive (98%), detecting nearly every tumor. (For breast cancer, however, the rate of detection was only 33%.) The test’s specificity for all the cancer types was greater than 99%, indicating a low risk for false-positive results.

Cancer tumors release into the bloodstream tiny traces of their mutated DNA. CancerSEEK is a multi-analyte blood test that analyzes those mutations in 16 genes that regularly arise in cancer tumors. The test also detects 8 protein biomarkers to detect tumors that do not release enough DNA into the blood. The recently reported case-control study will need follow-up with a larger cohort of cases. More important, the researchers will need to adjust the screening test to detect cancer at earlier stages. It is hoped that the test will cost less than $500 per patients.

Some factors are known to protect against ovarian cancer. Oral contraceptive use reduces the risk of ovarian cancer by as much as 80% in people age 40 to 59 years. Not only does longer duration of use provide more protection, but the effect lasts for as long as 15 years after oral contraceptives are discontinued.[6]  The same effect is seen with DMPA.[7] People who have had a term pregnancy before age 26 have a lower risk of ovarian cancer than those who have not, and risk goes down with each full-term pregnancy. Tubal surgery for permanent contraception is associated with a 40% to 50% reduction in the risk of ovarian cancer, and hysterectomy (without oophorectomy) with a 35% reduction. This may be explained by growing evidence that most ovarian cancers originate in the fallopian tube epithelium, both in those that are high-risk and in the general population.[8]

Risk factors, though weak, include a long interval of ovulatory cycles, low parity, delayed childbearing, body mass index of 30 kg/m², and infertility.⁵ However, the majority of people diagnosed with ovarian cancer have no risk factors.

[1] Cohen JD, Li L, Wang Y, et al. Detection and localization of surgically resectable cancers with a multi-analyte blood text. 2018 Science doi: 10.1126/science.aar3247.

[2] Policar M, Sawaya G. Screening Women for Cervical, Ovarian, and Breast Cancer. In: Hatcher RA, Nelson A, Trussell J, et al. (eds). Contraceptive technology. 21^st edition. New York: Ayer Company Publishers, Inc., in preparation.

[3] Moyer VA; U.S. Preventive Services Task Force. Screening for ovarian cancer: U.S. Preventive Services Task Force reaffirmation recommendation statement. Ann Intern Med2012 Dec 18;157:900-4.

[4] Buys SS, Partridge E. et.al. Effect of screening on ovarian cancer mortality: the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Randomized Controlled Trial. JAMA 2011 Jun 8;305(22):2295-303. doi: 10.1001/jama.2011.766.

[5] National Institute of Health Consensus Development Panel on Ovarian Cancer, NIH consensus conference. Ovarian cancer. Screening, treatment, and follow up. JAMA 1995;273:491–7.

[6] Rosenberg L, Palmer JR, Zauber AG. A case control study of oral contraceptive use and invasive epithelial ovarian cancer. Am J Epidemiol 1994;139:654–61.

[7] Wilailak S, Vipupinyo C, Suraseranivong V et al. Depot medroxyprogesterone acetate and epithelial ovarian cancer: a multicentre case-control study. BJOG 2012;119(6):672-7.

[8] Corzo C, Iniesta MD, Patrono MG, Lu KH, Ramirez PT. Role of fallopian tubes in the development of ovarian cancer. J Minim Invasive Gynecol 2017 Feb;24(2):230-234.