More than 69,000 American women were diagnosed with endometrial or ovarian cancer this past year. When caught early, these diseases are generally very treatable. Yet, 23,000 women in the US and nearly 10 times that worldwide die each year in part because of late-stage detection.
Named after Greek physician Georgios Papanikolaou, the Pap smear is a common screening test used to detect cancerous cells in the endocervical canal. Since its official introduction in the early 1940s, the Pap smear has reduced the incidence and mortality of cervical cancer in screened populations by an unbelievable 75 percent! Because of this, females older than 21 years of age are recommended to get tested every two-three years until around their seventh decade. However, during the average female’s course of Pap testing relatively few developments have occurred in the test itself. Perhaps the last major development was the switch to a liquid-based method that allowed both cytological analysis of cells as well as DNA collection to screen for human papilloma virus, which is a causative agent of cervical cancer.
Researchers at the Johns Hopkins School of Medicine have taken the Pap smear one step further by introducing the so-called PapGene test, which relies on genetic screening to detect common mutations present in ovarian and endometrial cancers. According to the paper in Science Translational Medicine:
The most important finding in this paper is that diagnostically useful amounts of cells or cell fragments from endometrial and ovarian cancers are present in the cervix and can be detected through molecular genetic approaches. Detection of malignant cells from endometrial and ovarian carcinomas in cervical cytology specimens is relatively uncommon. Microscopic examination cannot always distinguish them from one another, from cervical carcinomas, or from more benign conditions. In our study, 100% of endometrial cancers (n = 24) and 41% of ovarian cancers (n = 22) shed cells into the cervix that could be detected in materials collected as part of routine Pap specimens. In both types of cancer, tumors of low grade were detected. These findings, in conjunction with technical advances allowing the reliable detection of mutations present in only a very small fraction of DNA templates, are the foundations of the PapGene test.
In order to learn more about the research and how soon we may see it in the clinic, we corresponded with lead author and MD-PhD candidate, Isaac Kinde, who was recently named to the Forbes 30 Under 30 List in Science & Healthcare.
Shiv Gaglani, Medgadget: I’m aware of the molecular clock research from the Vogelstein research group, specifically with regards to pancreatic cancer which is generally only detected a decade or more after the first hit. How do ovarian and endometrial cancers compare?
Isaac Kinde: We are not aware of a quantitative analysis of the timing of tumor development in endometrial and ovarian cancers. However, observational studies following atomic bomb survivors, for example, predict that it takes at least 15 years for an ovarian cancer to develop. Because endometrial cancers are generally discovered at earlier stages than ovarian cancers, it is also likely that there is a similar window of opportunity for endometrial cancers. We are optimistic that detecting endometrial and ovarian cancers at early, more curable stages will lead to higher rates of patient survival, but the ultimate proof will only come after we complete a prospective clinical trial.
Medgadget: Do you have any data that compare the PapGene’s results to that of the Pap Smear on the same samples? Can you speculate on how much earlier endometrial or ovarian cancers may be detected using PapGene versus the Pap Smear?
[Put another way, about how much is gained by looking at DNA mutations versus cytological changes? I imagine that the gains are not so much from the time interval between DNA mutations and subsequent cytological changes, but rather from using the SafeSeqS approach (1 mutant template in 5,000 to 1,000,000 wild-type templates) which seems to be more sensitive and accurate than trying to find one dysplastic cell out of thousands of normals]
Kinde: We did not directly compare our test to conventional cytology-based Pap testing, but your hunch is likely correct. Our pilot study showed that detecting cancer-specific DNA mutations – at the low-levels permitted by Safe-SeqS – is a more sensitive approach than conventional Pap testing, which has been shown to have sensitivities of ~30 to 40% for endometrial cancers and only 15% for ovarian cancers. We do think it is likely that PapGene testing would detect a greater number of early (and late) stage endometrial and ovarian cancers than conventional Pap testing due to the higher sensitivity of our test.
Medgadget: In addition to genetic variability and location, do you think there are any other reasons that explain the lower sensitivity in detecting ovarian cancer?
Kinde: The relatively distant position of the ovaries compared to the proximity of the endometrium and the cervical opening, where the Pap specimen is collected, is likely the biggest contributor to the reduced ovarian cancer sensitivity. Other potential factors for the reduced ovarian cancer sensitivity could include the phase of the menstrual cycle the Pap specimen is collected, variability in the size of the endocervix (in accommodating the Pap smear collection brush), and subtle differences in sample collection techniques.
Medgadget: What are your next steps in terms of actually implementing the PapGene?
Kinde: Our immediate next step will be to perform PapGene testing on a larger number of women with and without cancer to get more accurate estimates of the test’s sensitivity and specificity. If our initial findings are validated by the larger study, we would proceed to conducting a prospective clinical trial.
For more information, watch this brief video,
Check out the press release: JOHNS HOPKINS SCIENTISTS USE PAP TEST FLUID TO DETECT OVARIAN, ENDOMETRIAL CANCERS