Hi, everyone again. I'm Natasha Phunjareun. I know it's hard to call my last name, so it's okay. Please feel free to call me Natasha. So I'm a geneticologist from Suvarnabhumi University in Thailand, and today I'm going to talk about the primary HPV for cervical cancer screening. Okay, so first we need to know about the goal of cervical cancer screening, that the goal of the screening is to prevent morbidity and mortality from cancer, and the prevention works by identification and destruction of the true cancer precursor. And so finding the lesion is not the objective of the screening, and we need to emphasize on true cancer precursors, which are persistent HPV infections, CN3, persistent CN2 and CN2N3 in non-adolescent women. And the transient HPV infection, low CL and CN1 are not the cervical cancer precursor. And we need to know that everything has their limitation, and attempts to prevent all cervical cancer are unrealistic and harmful. So we may cannot find some feel of the cancer in the youngest women, and if we would like to prevent all the cancer, to achieve total prevention would require the high sensitivity screen at the frequent interval with treatment of equivocal or mostly transient abnormality, and to do so maybe cause more harmful than helpful. And what is the potential harms from screening? It seems like screening is nothing bad, right, but there will be stigma, disrupted relationship, anxiety, and distress for the women, and they need to lose their time, and also the expense of investigation for the lesion that can be replaced by themselves, and they can get the pain and injury from the procedure like biopsy, endocervical curettage and treatment, and also the adverse pregnancy outcome. And we have to thank Dr. Harasu Housen, who get the Nobel Prize in 2008. So for nowadays, we know that most HPV infections are transient, especially in the young women, and the pre-cancerous changes like high seal can result from the persistence of HPV infection. The absence of HPV is highly predictive of absence of CAN. And the probability of clearing an HPV infection from a study in college women, the cumulative three-year incidence of HPV infection was 43%, and the median duration of the new infection was eight months, and also by 12 months after the infection, 70% of the women were no longer infected. And by 24 months, only 9% continue to be infected. And for the HPV prevalence and the cancer, and the prevalence of HPV was highest, like around 24% in women at age 20 to 24 years, and was progressively lower in older age groups. But the cancer incidence is highest around 45 to 55 years old. And let's talk about the HPV test cytology. So let me move some of this. Okay. So we know that the sensitivity from one of the study in 4,000 women who attend a clinic in Washington State, the sensitivity of the cytology is around 60%, while the sensitivity of the HPV testing is around 90%. With the specificity, around 90% for cytology and around 72% in HPV testing. But if we do look at the need to refer the patient to coproscopy, the HPV test is around 30%. It's like three times over the cytology. And another study is the Canadian Survey of Cancer Screening Trial, which is an RCT compare HPV and cytology. And this one find that the sensitivity of the cytology is around 55% for cytology and for the HPV testing is around 95%. And the specificity is around 97% for cytology and around 94% in HPV testing. This comes up with the rationale that we use for co-testing. And let's talk about HPV testing alone and also the co-testing. Everyone may think that, oh, it's good that we use it together. So it will combine the sensitivity. So from the Portland Kaiser study in Portland, it's like a study in the 23,000 women compared between HPV testing and co-testing and so the cytology alone. So they found that the sensitivity of the HPV is around 75% and the sensitivity of the co-testing is around 86%, but the negative predictive value is around the same. And under last study in Northern California, it's just prospective study in 300,000 women. And they found that in the negative cytology did not decrease the risk of the CN3 plus for the HPV negative women at both three years and five year. But their positive cytology can modify the risk for the positive HPV test at three and five year. But for the HPV negative test, if you see, they say that it's not increased the risk, but if you see the number, it is statistically different like with the P value, but it's not increased the risk to the substantial level. So the HPV, the negative HPV identify a fairly low risk group where the cytology is negative or not. So from the last Athena trial in 40,000 women have cytology and also high-risk HPV positive testing, and they calculate the performance of three screening strategy over three years. The first strategy is cytology. The second strategy is hybrid, that they will do cytology for 25 to 29 years old or co-testing for women 30 years old or more. And for this, the hybrid strategy, they will do corposcopy only if both tests are positive. If the HPV positive but the cytology negative, the women will get re-screened in one year. And the third one is the primary HPV screening. And from this study, they found that the sensitivity, let's say in more than 30 years old, for HPV testing is around 72%, but the hybrid is around the same, it's around 69%. But you may see that it's a little bit just like different. And so from this study, they conclude that the HPV primary screening with triage using HPV 16 and 18 genotyping and cytology increase sensitivity to detect CN3 compared to cytology, and it increases around like almost 30%. And the cytology failed to detect around 50% of CN3 plus within women 25 to 29 or so, more than 30 years. From the Athena trial, this come up with the interim clinical guideline in 2015. And this one recommend that if you do the primary HPV screening, and then the HPV is positive, they recommend to do high genotyping. If the HPV 16, 18 positive, go to corpuscopy. But if it's other HPV, other high-risk HPV, go to do cytology, and go to corpuscopy only if the abnormal cytology is finding. So another study by that, only 3.5% of pre-cancer and 5.9% of cancers were preceded by HPV negative cytology positive result. So this means the cytology component contribute only five cases per million women per year to the sensitivity of the combined test. And for now, the FDA approved test for primary HPV screening has only COBAS HPV testing and also VDM quality HPV assay. And the purpose for HPV positive triage can be the first one that we talk a lot is about cytology because of the high specificity of cytology, make it suitable for triaging HPV positive cases. But the subjective nature of cytology affect interpretation. And also the awareness of the positive HPV status may lead to more accurate detection, or sometimes even more, or even over-detection. The second one is the HPV genotype triage as we talk. And other marker that talking about is the molecular test that like P16, Ki67, that can be used to triage HPV positive cases. And also other methylation marker have been investigated to differentiate the transient HPV of pre-cancerous lesion or the infection. And the last one is CIA that has been used to triage HPV positive cases in low-resource setting with an additional benefit of providing treatment at the same time. And this advantage of HPV-based primary screening is because it's twice as likely of the screen patient needing to get a corposcopy and lower specificity and potential to bias subsequent reflex cytology reporting, as I talked about, and as yet unproven long-term proof of equivalent and outcome and cost-effective compared to consensus guideline and optimum screening interval and follow-up protocol have yet to be determined. And let's talk about the screening guideline. The first one is not exactly the guideline, but it's the WHO Global Call for Action. So they talk about 70% of women screened with an HPV test at 35 and 45 years of age. And the first guideline that come out and talking about primary HPV is the USPSTF in 2018. And for the USPSTF recommendation, for women aged 30 to 65, they recommend any one of the following, like it's all the same, like for cytology alone every three years, FDA approved primary high-risk HPV testing alone every five years, or co-testing every five years. The second one is the American Cancer Society guideline in 2020. For this guideline, they change quite a lot, and they talk about their stats with screening at 25 years old. And at 25, primary HPV test alone every five years is preferred. And for the primary HPV, they talk to us about use an FDA-approved HPV test for primary screening. And the co-testing or cytology can be like acceptable in the case that, or in the place that cannot do the primary HPV. So the ACCP talk about the guideline of the ACS and also USPSTF, and they support the guideline, but still they don't change that guideline. And also the ACOG recommendation, oh, sorry. Okay. They say that other, the cervical cancer screening option have expanded, but they are like mentioned about our strategy are effective. And the specific strategies selected is less important than consistent adherence to routine guidelines. So, and they still recommend to screen at age 21. So if we use the, like follow the USPSTF guideline, what will happen in the future? So the fewer cervical cytology tests will be, because primary high-risk HPV screening option will add for women more than 30 years old. And by this way, we'll get the more corpuscopy. And also maybe in the future, the healthcare plan, the health plan may consider limiting the use of co-testing or surveillance after abnormal cytology or treatment. And the update of the management guideline from ACCP for, from the 2018, no, 2019, sorry. This update is like to replace the interlinked guideline. And they talk about that when the primary HPV screening is used, they prefer to do the reflex cytology for all positive HPV tests, regardless of the genotype, even though the patient has 16 and 18. So they would like to do the cytology. And you may think that, oh, but for this patient that has positive for 16 and 18, they may go to do corpuscopy. Why do we need to do cytology? And I will talk about it later. And even though, and the next paragraph is that if the primary HPV screening test is positive for HPV 16 and 18, but the reflex cytology from the same lab specimen is not available, so refer for corpuscopy before getting the cytology is acceptable. But with this group of patient, when you, when the patient come to get the corpuscopy at that visit, please do the cytology. As you can see that the guideline is so like obsessed about cytology, because the reason is that the cytology provides the further information for the risk-based management. Let me give some example. If the patient, for the first paragraph, if the patient has HPV 16 and you get the cytology, and then the cytology will come back with high-field cytology. So her risk for CN3 is around 60%, and she should be given the option of expedited treatment. This is the first one. And then for the second one, if the HPV is 16 positive, and then you cannot do the cytology from the same lab specimen, and you take the patient go to do corpuscopy, and then you get the cytology at that time, and then the corpuscopy biopsy result is come back with with RCN2 and 3, but the cytology come back with high-grade lesion, like high seal, maybe you still consider treatment in this group of patient. So the warning of the recommendation, the clinician, patient, payers, or everyone should not view the recommendation as dictated. And your set of guidelines may reasonably conclude that following guidelines will be a mistake for some patients. And screening in excess of guidelines has been shown to cause harm to patients and to increase costs. And this is just like the key counseling message for women who think positive. I will not talk about it, but Susan can send the file on the slide. And the conclusion that I would give for today is from American Cancer Society 2002, that the biggest gain in reducing cervical cancer incidence and mortality would be achieved by increasing screening rate among women who have not been screened or who have not been screened regularly. It's not what strategy that we use, but it's how can we get them to screen regularly. Thank you.

geneticologist

HPV screening

cervical cancer

precancerous HPV infections

screening guidelines