Genetic PAP test

Tagged PAP smear; Posted 11 years ago

In the future, PAP smears will do a lot more than just screening for cervical cancer. DNA collected on the PAP smear sample will be able to identify mutations that indicate the presence of endometrial and ovarian cancer in the future.

The good old PAP smear developed from a simple glass slide smear was introduced mid last century. George Pap was a physiologist and interested in the hormonal changes throughout the menstrual cycle. Some 100 years ago Mrs Pap ended up being one of the most smeared women in history. Accidently George stumbled across a case of a woman who apparently was diagnosed with cervical cancer not too long at her visit at Dr Pap’s place. He went back to review the slide from this poor woman – only to find quite different cells than the ones he typically found on the smear of his dear wife.

Ten years ago we moved to a liquid-based collection system detecting not only abnormal cells but also HPV that causes cervical cancer. HPV testing turned out to be more sensitive for the detection of recurrence of CIN than the conventional smear.

In January this year, researchers from Johns Hopkins in Baltimore went a step further presenting a rather revolutionary concept. They tested 46 liquid based cytology samples from patients diagnosed with endometrial or ovarian cancer. They hypothesised that cancers of the endometrium and the ovaries would shed some cancerous material through the cervical canal and the DNA of these cells would be detectable through the PAP smear.

Prior to that, all patients’ tumours were tested for mutations. A total of 22 mutations were found in those cancers. The detection rate of those mutations were:

• In patients with endometrial cancer mutations were detected in all (100%) patients.
• In patients with ovarian cancer mutations were detected in 40% of patients.
• In patients without cancer no mutations were detected.

We all realise that this new approach is not ready to be used on patients in clinical routine as yet. The cost of sequencing would be prohibitive at present but costs can come down very quickly if need be. In addition, the results need to be validated by larger samples in other centres.

I like three aspects about this research: First, no healthy patient got diagnosed with a mutation. This is important because it limits the harm that we involuntarily do to patients when we introduce new technology. By contrast, HPV testing is positive in virtual all patients who are sexually active, which precludes HPV testing from being a screening test.

Secondly, all endometrial cancers were diagnosed by gene sequencing from the PAP smear. In the past, screening for endometrial cancer failed big times. Screening would be urgently needed for the ever-growing number of young patients diagnosed with Lynch syndrome. Transvaginal ultrasound measures the endometrial thickness, which correlates with the risk of cancer. However, its accuracy is very low because other conditions also can cause a thickened endometrium and some cancers such as serous carcinomas don’t necessarily present with a thickened endometrium. Imagine, a PAP alarms because your patient is being diagnosed with endometrial cancer. At the same time, the gene sequencing will inform you how to treat this patient. Will this patient respond to hormonal treatment (Mirena), some systemic targeted treatment (e.g., mTor inhibitor) or does she require radical surgery? In that case, the PAP smear might even advise in advance what kind of postoperative treatment she might respond to.

Third, only 40% of ovarian cancers were picked up by the test, which is poor. However, it is probably still heaps better than the current ultrasound and CA125 combo that we offer our patients at present. Massive resources have been allocated to develop ovarian cancer-screening tools, but so far the potential harms of screening outweigh the potential benefits.

With a lot of research we might see that the PAP smear develops to not only a screening tool for cervical but generally for gynaecological cancer. Would that constitute value for women to “like” their PAP smears better and motivate them to attend their health checks regularly?