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Screening for Familial Ovarian Cancer: A Ray ofHope and a Light to Steer byKara C. Long and Noah D. Kauff, Memorial Sloan-Kettering Cancer Center, New York, NY

See accompanying article doi: 10.1200/JCO.2011.39.7638

Since theidentification of cancer antigen(CA)125in 1981,1 this

serum marker has been extensively evaluated as a potential screening

test for ovarian cancer. At approximately the same time, pelvic ultra-

sonography was also suggested as a potential alternative approach to

screen for this disease.2

Despite the initial promise of both of thesetechniques, screening for ovariancancer in the general population has

remained an intractable challenge.

In order for a cancer screening program to be efficacious, there

are several essential requirements of both the screening test and the

disease (adapted from Mulley3): (1) the screening test must be sensi-

tive enough to detect cancer at an earlier point in its natural history

(generally indicated by stage shift); (2) the test must be sufficiently

specific to provide an acceptable positivepredictive value (for ovarian

cancerthishas been somewhatarbitrarily set ata minimum of 10%, ie,

there should be no more than nine surgeries performed due to false

positive screening tests for each case of invasive cancer diagnosed);

and (3) treatment at time of screen detection must improve outcome

compared to treatment delayed until symptoms appear.

Unfortunately, for ovarian and fallopian tube cancer in the gen-

eralpopulation, these criteriahave notyetbeen definitively met. While

both ultrasound and CA-125 are highly sensitive for detecting ad-

vanced stage cancer,neitherhas proved as goodat detecting early stage

disease. During the first four ovarian cancer screening rounds of the

Prostate, Lung, Colorectal and Ovarian (PLCO) screening trial, in

which 78,216 women aged 55 to 74 years were randomized to either

usual care or ovarian cancer screening with annual transvaginal ultra-

sound (TV US) for 4 years and annual CA-125 serum testing for 6

years, 42 (69%)of 61 incidentinvasive ovarianand fallopian tube were

screen detected. However, 28 (67%) of these 42 screen-detected can-

cers (and 76% of all cancers in women undergoing screening) werestage III or stage IV cancers.4 Further, given the low annual incidence

of invasive disease (0.07% during the first 3 years of the PLCO study),

thepositive predictive value of screen-indicated surgical biopsy was

only 3.2% on prevalent screen and 4.9 to 9.5% in each of the first

three annual incident screens, despite the combination of TV US

and CA-125 leading to a biopsy, yielding a specificity greater than

98% in all rounds of screening. Given the lack of stage shift, it was

not surprising that when the final results of the PLCO trial were

reported last year, there was no improvement in mortality in the

screened group. Additionally, more than one out of 30 women

participating in the screening arm underwent surgical exploration

due to an abnormal screening result, with only 6.3% of these women

having an invasive cancer identified.5

Do these discouraging results also suggest that ovarian cancer

screening is unlikely to benefit women at familial risk of ovarian

cancer? Before we reach that conclusion, it is important to acknowl-edge several important differences between sporadic and familial

ovarian cancer. First, the incidence of ovarian cancer in women with

BRCA1or BRCA2 mutations (the most common known causes of

familialovarian cancer) over the age of 50 years is 1.0 to 2.5% per year

and 0.4-0.8% per year respectively.6 Applying a screening approach

similar to that employed in the PLCO trial with 98% specificity,

positive predictive values of 16% to 56% are theoretically achievable.

Furthermore, recent research on the pathogenesis of pelvic serous

cancers has led to the hypothesis that our current staging system may

notreflect thenaturalhistory of thedisease.7Withthisinmind,amore

appropriate target for a screening test may be low-volume stage III

disease,instead of necessarilystage I or IIdisease.8Lastly,the biologyof

inherited ovarian cancer may be inherently different than that ofsporadic ovarian cancer. Multiple studies have demonstrated im-

proved survival forBRCA-associated ovarian cancer,9-13 with at least

one of these studies suggesting that this effect is independent of plati-

num sensitivity.10 These different biologic features may allow treat-

ment of familial ovarian cancer at time of screen detection to be more

efficacious than has been the case in the setting of sporadic ovar-

ian cancer.

In the article that accompanies this editorial, Rosenthal et al14

present preliminary results from the United Kingdom Familial Ovar-

ian Cancer Screen Study (UK FOCSS), the first of two large-scale

prospective trials testing the hypothesis that ovarian cancer screening

maybe beneficial inwomen at familial risk. Inthisseries, 3,563 women

at greater than a 10% risk of ovarian or fallopian tube cancer were

screened with annual TV US and annual CA-125 for a mean of 3.2

years. At the time of consent, women were counseled that risk-

reducing salpingo-oophorectomy (RRSO) was the recommended

management; however, the majority of participants declined or de-

ferred this approach throughout the course of the study, highlighting

the need for screening options in these patients. This well-designed

and -executed prospective study, while not randomized, provides the

best data to date evaluating the role of ovarian cancer screening in

women at familial risk.

As noted above, an effective ovarian cancer screening regimen

must at a minimum be associated with a clinically meaningful stage

JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L

2012 by American Society of Clinical Oncology 1Journal of Clinical Oncology, Vol 30, 2012

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shift at diagnosis. In the UK FOCSS, only six of 23 (26%) cancers not

associated with Lynch syndrome in women screened in the previous

year were diagnosed at stage IIIc or higher as compared with six of

seven (86%) cancers in women not screened in the year before diag-

nosis (P .009). Further, while not statistically significant, there were

also trends towards improvement in optimal cytoreduction (91.3% v

57.1%) and overallsurvival (mean overallsurvival, 71.9months v48.4

months) in patients screened per protocol as compared to those notscreened in the previous year. These results suggest that a clinically

meaningful stageshift occurred in women who werescreened accord-

ing to protocol as opposed to women whounderwent delayed screen-

ing.Additionally,the false-positiverate wasacceptable,withonly1.5%

of women undergoing surgery prompted by false-positive screening re-

sults,ultimately achievinga 25.5% positive predictive value forscreening.

While the study was not designed to evaluate the impact of screening on

familial ovarian cancer mortality, these results provide a ray of hope that,

at least for patients at risk of familial ovarian cancer, an effective ovarian

cancerscreening programmaybe achievable.

Giventhese promising results,what direction shouldfuture stud-

ies pursue? The UK FOCSS clearly demonstrates the importance of

undergoing screening at the prescribed intervals and the negativeimpact of delayed evaluation. Therefore, for the ongoing phase II of

this study, the screening interval for CA-125 determination has been

decreasedto 4 months, andthe threshold andwork-up forrepeat tests

is now protocol driven. With these changes, as well as the incorpora-

tion of the Risk of Ovarian Cancer (ROCA) algorithm to improve

both the sensitivity and specificity of CA-125,15 it is hoped that the

results of phase II will support the use of ovarian cancer screening as a

viable alternative to RRSO, at least in the premenopausal years.

The UK FOCSS also provides direction in regards to whom

screening efforts should be targeted. The UK FOCSS trial included

onlyparticipants meeting stringent familial riskcriteria. Specifically, if

participants did not have a documented mutation in BRCA1, BRCA2or a mismatch repair gene associated with Lynch syndrome, the par-

ticipant had to have both a family history of ovarian cancer and a first

degree relative affectedwitheither ovarian,early onset breast or colon

cancer. These criteria specifically excluded women from site-specific

hereditary breast cancer families who are frequently thought to be at

riskfor familial ovariancancer,buthavepreviouslybeenshown not to

be at increased risk for this disease in the absence of a BRCA1 or

BRCA2mutation.16,17 Despite these relatively rigid inclusion criteria,

almost all the cancers occurred in patients with documented muta-

tions in known ovarian cancer susceptibility genes. During the course

of the study, 30 (5.6%) of 538 known BRCA1 or BRCA2mutation

carriers were diagnosed with invasive cancer. Similarly, three (4.6%)

of 65 mismatch repair mutation carriers were found to have invasivecancer. However, among the 2,960 participants without a known

mutation, only four (0.14%) had an invasive cancer diagnosed over

the mean3.2 years of follow-up. Thistranslatesto an annual incidence

of one in 2,368 which is likely not different than the one in 2,785

annual incidence of invasiveovarian cancer seenin women over age50

years in the United States in 2008.18

Given these results,it likely can beargued that family history isno

longer an acceptable surrogate for genetic risk of ovarian cancer and

that genotyping should be a requirement for inclusion in trials assess-

ing screening in individuals at inherited risk, as has similarly been

argued for therapeutic trials in ovarian cancer.19-21 This approach has

been taken in the recently completed, but not reported, Gynecologic

Oncology Group0199 trial, a prospective study of RRSO andlongitu-

dinal CA-125 screening among women at increased genetic risk of

ovarian cancer.22 These results are expected in 2014 and combined

with the results of phase II of the UK FOCSS should provide the first

clear guidance as to whether screening for ovarian and fallopian tube

cancer will be a viable alternative to risk-reducing surgery for women

at inherited risk for these cancers.

Until these results are available, the results of phase I of the

UK FOCSS support the current recommendation that women at

inherited risk who decline RRSO in their 30s should consider screen-

ing for ovarian cancer from approximately age 35 years until they

undergo definitive risk-reducing surgery as recommended no later

thantheir early 40s.23,24 Further, the resultsprovidestrong supportfor

the proposition that neither screening nor risk-reducing surgery

should be offered to women at putative familial risk until formal

genetic risk assessment and counseling with appropriate genetic test-

ing has been completed.

AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the followingauthor(s) and/or an authors immediate family member(s) indicated afinancial or other interest that is relevant to the subject matter underconsideration in this article. Certain relationships marked with a U arethose for which no compensation was received; those relationships markedwith a C were compensated. For a detailed description of the disclosurecategories, or for more information about ASCOs conflict of interest policy,

please refer to the Author Disclosure Declaration and the Disclosures ofPotential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or AdvisoryRole:Noah D. Kauff, Pfizer (C)Stock Ownership:NoneHonoraria:NoneResearch Funding:NoneExpert Testimony:Noah D. Kauff,Pfizer (C)Other Remuneration:None

AUTHOR CONTRIBUTIONS

Manuscript writing:All authorsFinal approval of manuscript: All authors

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