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Joining FORCES is the FORCE newsletter with news, views and supportive information for individuals concerned about hereditary breast and ovarian cancer.

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Improving Ovarian Cancer Screening

by Lisa Rezende, PhD

Many women with mutations in BRCA1 or BRCA2 undergo close screening for ovarian cancer until they complete childbearing and/or reach age 35-40, when surgical removal of ovaries and fallopian tubes (risk-reducing salpingo-oophorectomy) is recommended. Current National Comprehensive Cancer Network (NCCN) guidelines recommend that BRCA1 or BRCA2 mutation carriers with intact ovaries consider ovarian cancer screening twice a year using pelvic exam and transvaginal ultrasounds, and a blood test to look for increases in the CA-125 protein.

While these tests are the best we have, they are far from perfect. Even with heightened screening, ovarian and fallopian tube cancers are usually found at late stages (stages 3 or 4). This means that a woman can have normal images on transvaginal ultrasound and normal CA-125 levels but still have cancer. Some women have false positive results: abnormal findings on transvaginal ultrasounds and elevated levels CA-125 levels even when no ovarian cancer is present, resulting in more extensive testing, and in some cases, surgery to confirm that the changes are cancerous.

Finding better methods to detect ovarian cancers before they progress is a high research priority for our community. Ideally, a good biomarker for screening would:

  • show changes at the early stages of ovarian cancer.
  • be measurable in the blood stream (blood tests are relatively noninvasive and inexpensive).

Scientists are searching for new biomarkers that may indicate early-stage ovarian cancer. One candidate is a protein known as HE4. Early studies looked at women with both benign and cancerous pelvic masses, and compared their CA-125 to HE4 blood test results. HE4 levels identified more ovarian cancers than CA-125 alone. While this study pointed to the promise of HE4 as an ovarian cancer biomarker, proving that it is useful as an ovarian cancer screening test in patients without symptoms requires further research.

Another study tested the use of HE4 combined with CA-125, either as an initial screening test or using HE4 levels to confirm abnormal findings on CA-125. The study included 1,172 women at high risk for ovarian cancer from one or more of the following:

  • a BRCA1 or BRCA2 mutation
  • a strong family history of ovarian cancer
  • other ovarian cancer risk factors

The women were randomly assigned to one of two groups. The first group initially had blood tests to determine levels of both HE4 and CA-125. The second group was initially screened using CA-125 alone; HE4 levels were then tested only if the CA-125 values were abnormal. Both groups were given transvaginal ultrasounds if they had elevated CA-125 and/or HE4 levels.

Over three years, 37 of the women had at least one abnormal screening (transvaginal ultrasound, CA-125, and/or HE4). Six of the women identified through screening had surgery to remove their ovaries and fallopian tubes, and two were diagnosed with ovarian cancer at the time of surgery. Among women with abnormal findings during screening:

  • both women who had abnormal findings on all three screens (transvaginal ultrasound, and elevated CA-125 and HE4 levels) were diagnosed with ovarian cancer at the time of surgery.
  • both ovarian cancers uncovered during screening were advanced (stage 2c or 3c).
  • two women with elevated CA-125 values but normal HE4 values and normal transvaginal ultrasound images were later diagnosed with other cancers (one recurrent breast cancer and one pancreatic cancer).
  • one woman with elevated CA-125 and HE4 values but normal transvaginal ultrasound images was later diagnosed with lung cancer.

Over the course of the study, 102 women with normal screening results elected to have their ovaries and fallopian tubes removed to reduce their cancer risk. Of these women:

  • five were diagnosed with precancer (stage 0) or early-stage (stage 1a) ovarian or fallopian tube cancer or pre-cancer at the time of surgery.
  • one woman who was diagnosed with fallopian tube cancer had elevated CA-125 levels before surgery.

The study shows the potential of using HE4 as a biomarker to confirm elevated CA-125 values. While this is an early study, the authors note that using HE4 as a primary screening test increased false positive results. However, using it as a secondary test to follow up an abnormal CA-125 result showed more promise, and could decrease false positives generated by using CA-125 alone. This study was relatively small, few cancers were detected, and screening did not identify any early (stage 1) cancers. More research is needed before the use of additional biomarkers in ovarian cancer screening is recommended.

Moore RG, Brown AK, Bast RC, et al. “The use of multiple novel tumor biomarkers for the detection of ovarian carcinoma in patients with a pelvic mass.” Gynecological Oncology vol. 108, no. 2 (2008): 402-8.

Karlan BY, Thorpe J, Urban N, et al. “Use of CA-125 and HE4 serum markers to predict ovarian cancer in elevated-risk women.” Cancer Epidemiology, Biomarkers, and Prevention vol. 23, no. 7 (2014): 1383-93.

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