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Developing effective screening tool remains ‘holy grail’ of ovarian cancer research
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Breast, colorectal and ovarian cancers are among the most common cancers that affect women, according to the American Cancer Society. The mortality rates associated with these cancers in women vary drastically. This year, there will be an estimated 41,760 deaths attributed to breast cancer, 23,240 deaths attributed to colorectal cancer, and 13,980 deaths attributed to ovarian cancer in the United States.
Oncologists have focused on reducing the occurrence and mortality rates of these cancers through patient education, prevention and screening. Within the past 2 years, more than half (64%) of women aged 40 years and older underwent a mammogram to screen for breast cancer, according to a report from the American Cancer Society. Additionally, according to that same report, 83% of women aged 21 to 65 years were up-to-date on cervical cancer screening and 62% of women had completed some form of colorectal cancer screening in 2015.
Although cancer screening has not been directly linked to increased survival rates, screening does increase the chances of catching cancers at early stages, which can help increase the success of available treatments. Unfortunately, for ovarian cancer, screening options are limited.
“Currently, there is no effective screening option for ovarian cancer in women who are considered to have the average population risk, or even for women at high risk,” Karen H. Lu, MD, chair of the department of gynecologic oncology and reproductive medicine at The University of Texas MD Anderson Cancer Center, told Healio. “Having said that, there’s still a huge need [for one], because we know that the vast majority of women who are diagnosed with ovarian cancer are diagnosed at later stages when cure is extremely difficult.”
Early diagnosis leads to better survival
Less than half (47.4%) of women diagnosed with ovarian cancer reach the 5-year survival threshold after initial diagnosis, according to statistics from the NCI.
Approximately 15% of ovarian cancer occurrences are diagnosed at a localized level, which is the earliest form of diagnosis. The 5-year relative survival rate for women diagnosed with localized ovarian cancer is 92.3%. Although this survival rate is promising, more than half (59%) of diagnoses occur during the distant stage, which is considered late-stage. The 5-year relative survival rate for women diagnosed with distant stage ovarian cancer is only 29.2%.
Screening recommendations
The overall consensus among major medical societies is that ovarian cancer screening is not recommended in the general population. In its most recent recommendation in 2018, the U.S. Preventive Services Task Force (USPSTF) strongly recommended against screening asymptomatic women who are not known to have a high-risk hereditary cancer syndrome, giving the recommendation a D grading.
The task force wrote that it found adequate evidence that screening for ovarian cancer does not reduce ovarian cancer mortality and that the harms associated with screening are at least moderate and may be substantial in some cases. For example, a false-positive test result could lead to the unnecessary removal of one or both ovaries and fallopian tubes.
The USPSTF based its decision on results from the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS; n = 202,638) as well as the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial (n = 68,577).
The UKCTOCS trial had two intervention groups and a no-screening control group. Women were randomized to either screening with CA-125 serum testing, with triage and follow-up determined by risk of ovarian cancer algorithm (ROCA), or to yearly transvaginal ultrasound.
ROCA was used to assess the change in CA-125 levels over time. If a woman’s CA-125 level substantially increased compared with the prior year, she underwent transvaginal ultrasound screening.
“This method has the advantage of identifying a baseline CA-125 range for each woman, instead of using a static, single-value cutoff as was used in the PLCO study,” Lu wrote in an editorial published in JAMA.
She added that findings from the UKCTOCS trial have shown that establishing individual CA-125 baseline values can improve the diagnostic accuracy of the biomarker.
After a median follow-up of 11.1 years, ovarian cancer mortality was not significantly different among the control group and two intervention groups (0.35% in the control group, 0.32% in the transvaginal ultrasound group, and 0.32% in the CA-125 ROCA group). There was also no significant difference in mortality risk in the transvaginal ultrasound (HR = 0.91; 95% CI, 0.76-1.09) and CA-125 ROCA groups (HR = 0.89; 95% CI, 0.74-1.08). Still, Lu noted that there were 15% fewer deaths among women who were screened, as well as “a significant shift toward detecting earlier stage [and] low-volume ovarian cancers in the ROCA group as compared with the control group (40% vs. 26%),” she wrote in the editorial.
“Although the reduction in mortality in the ROCA group in the UKCTOS trial did not reach statistical significance, the authors pointed out that there appeared to be a delay in observing the benefit of screening on mortality,” she added.
Delayed screening benefits have been observed in other studies, with most of the benefit occurring years later, according to Lu. Researchers from the UKCTOCS trial plan to further investigate this delayed benefit. Lu anticipates that updated data from the trial will be released in the next year.
Meanwhile, results from the PLCO trial also failed to show a significant difference in ovarian cancer mortality between women who underwent six rounds of screening (four with CA-125 and transvaginal ultrasound and two with CA-125 alone) and women who received usual care (0.34% vs. 0.29%; RR = 1.18; 95% CI, 0.82-1.71).
“When we think about the risk-benefit ratio of screening women who are otherwise healthy, the thing that we always worry about with cancer screening is, can we potentially harm the patient?” Lu said. “And we know that if a screening test is not specific enough, then we could have false positives during the screening and end up causing a lot of worry as well as potentially [lead to] some downsides such as having to have unnecessary surgery.”
In the PLCO trial, 3,285 women had false-positive results. Among them, 1,080 underwent surgical follow-up, 15% of whom experienced at least one serious complication.
Lu noted that a good screening test must meet a certain criterion and be sensitive enough to pick up the disease at an early stage, but also have a very minimal false-positive rate so the safety of patients is not jeopardized. She also firmly agrees with the recommendations of the USPSTF.
“Right now, there is not a screening test that fulfills that bar that is sensitive enough to pick it up in its earliest stages, but does not cause harm,” Lu said. “We have not yet discovered a screening test, or a screening strategy that fulfills everything that will be effective in screening healthy asymptomatic women.”
Tremendous need
Lu emphasized the tremendous need to identify an effective ovarian cancer screening strategy. She said there is research looking at the validity of both blood-based biomarkers — including microRNA and circulating DNA in the blood — and DNA markers in cervical fluid. However, she said it is still too early to determine the strengths of these biomarkers.
“It remains the holy grail for ovarian cancer research, if not one of the most important unmet needs in ovarian cancer research,” she said. “There’s been this continuous effort in the research community to identify effective markers, including markers to complement CA-125, which thus far is a good marker, but not the perfect marker for screening for ovarian cancer.”
A study recently published in Cancer Prevention Research assessed the diagnostic accuracy of 92 serum protein biomarkers. The researchers identified 40 proteins that had an estimated area under the ROC curve of 0.70 or greater, “suggesting their potential to serve as biomarkers for ovarian cancer,” they wrote. Adding five of the proteins to CA-125 in a multiprotein classifier improved the diagnostic performance of CA-125 alone. The sensitivity of the assay increased from 93.4% to 98.4% at a specificity of 98%.
According to Lu, there have been additional efforts to assess the sensitivity and safety of different imaging technologies, as well as imaging modalities that could work as a second-stage for screening.
“I think the other area, in terms of improving screening, is kind of the concept of not just one marker, but a strategy where you would have an initial blood test and then you would go to a second, for those who have an abnormal blood test, triage test which in the past has been ultrasound to confirm the initial blood screening test,” she said.
Optimism
Although she is optimistic that there will be more advances in screening, Lu said it may be a slow road ahead.
“Even though ovarian cancer is devastating for individual women, it is still fairly rare in the general population,” she said. “And to do the type of studies that are needed to show that a screening test has a significant impact on ovarian cancer mortality, that can often take a decade.”
One way around the lack of screening options, according to Lu, is to focus more effort into identifying women who have high risks for ovarian cancer, particularly in women with BRCA1 and BRCA2 mutations.
“These women, instead of having a 1.5% lifetime risk of ovarian cancer, can have up to a 40% lifetime risk of ovarian cancer,” she said. “So, when we can identify those women, we can institute preventive methods, and as we work to develop early detection strategies, part of that strategy has to be better identifying high-risk women.”
References:
American Cancer Society. Cancer Facts for Women. https://www.cancer.org/healthy/find-cancer-early/womens-health/cancer-facts-for-women.html. Accessed March 27, 2019.
American Cancer Society. How Common Is Breast Cancer? https://www.cancer.org/cancer/breast-cancer/about/how-common-is-breast-cancer.html. Accessed March 27, 2019.
ASCO. Colorectal Cancer: Statistics. https://www.cancer.net/cancer-types/colorectal-cancer/statistics. Accessed March 27, 2019.
American Cancer Society. Key Statistics for Ovarian Cancer. https://www.cancer.org/cancer/ovarian-cancer/about/key-statistics.html. Accessed March 27, 2019.
Cancer Prevention & Early Detection Facts & Figures. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/cancer-prevention-and-early-detection-facts-and-figures/cancer-prevention-and-early-detection-facts-and-figures-tables-and-figures-2018.pdf
https://www.who.int/cancer/detection/en/. Accessed on March 21, 2019.
National Cancer Institute. Cancer Stat Facts: Ovarian Cancer. https://seer.cancer.gov/statfacts/html/ovary.html. Accessed March 27, 2019.
U.S. Preventive Task Force. JAMA. 2018;doi:10.1001/jama.2017.21926.
Lu KH, et al. JAMA. 2018;doi:10.1001/jama.2017.21894.
Buys SS, et al. JAMA. 2011;doi:10.1001/jama.2011.766.
Skubitz A, et al. Cancer Prev Res. 2019;doi:10.1158/1940-6207.CAPR-18-0221.
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