Dear Colleague,We offer a suite of diagnostic options for cervical cancer screening. These options include the following:• Conventional Pap Smear• Liquid Based Cytology (LBC) – BD SurePath• HPV PCR Assay – Seegene Anyplex II HPV HR Detection• HPV HC2 Assay – Digene HC2 HPV DNA Test• Cervical Self Collection – Delphi Screener (used in conjunction with Digene HC2 HPV DNA Test)

At Quantum, we seek to support and empower doctors through education and by providing the necessary diagnostic tools to help you make more informed decisions for patients. This article aims to do that by providing you with the latest update on the increasingly important role of HPV screening in cervical cancer detection and prevention. We believe that to remain relevant and to help you deliver the best outcomes for patients; we have to continue to innovate and to bring you the most up to date in actionable diagnostic tests. Cervical cancer is the third most common cancer in Malaysian women (Malaysia National Cancer Registry Report 2007). 45% of cases reported were diagnosed at Stages 3-4 which means poorer outcomes and lower survival rates. The expected 5 year survival rate of patients diagnosed with Stage 4 Cervical Ca is 15%. This survival rate rises to almost 90% in patients diagnosed at Stage 1. This highlights the importance of early detection in ensuring patients have a better chance of survival.The introduction of cervical cancer screening programmes and HPV vaccination has not achieved the desired effect of reducing our cervical cancer mortality rates. There are a number of factors for this, including poor coverage by the national screening programme as well as very poor recall rates following baseline screening. Our national mortality rate from cervical cancer remains high at 4.7 ASR deaths per 100 000 (Globocan 2012) – almost double that of Singapore at 2.6 ASR deaths per 100 000. This huge difference in our mortality rates mean that there is still much that can and needs to be done.The causal association of persistent HPV infection and the development of cervical carcinoma is well established. This association together with the strong evidence base for HPV as an accurate screening tool is the reason why HPV co-testing has been introduced into the national screening programmes of Australia and the Netherlands. As more and more studies continue to add strength to the evidence base of HPV screening in cervical cancer detection, we will continue to see this trend grow.

Based on the current evidence available, our key messages are as follows:1. HPV co-testing significantly increases the detection of CIN2+ lesions at screening compared with cytology alone. Co-testing (vs cytology alone) resulted in a significant 40% increase in detection of CIN2 lesions or worse – early

detection of premalignant CIN allows early monitoring and treatment to prevent disease progression.1

2. HPV testing alone is more sensitive than cytology alone in the detection of CIN 3+ lesions. HPV testing alone has a 76.1% test sensitivity vs cytology alone which has a 46.8% test sensitivity. The specificities of both tests are similar.2,3

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3. Triage of positive tests by genotyping (into high and low risk genotypes) strikes an appropriate balance between test utilization and safety. This increases detection rates of premalignant lesions without increasing unnecessary patient referrals for colposcopy. ,3

4. HPV testing is significantly more accurate than repeat cytology at triaging patients with ASCUS following cytological screening. HPV testing produced higher pooled sensitivity with similar specificity – therefore is a useful tool in decision making when using cytological screening for cervical cancer.4

5. Liquid based cytology as a means of specimen collection allows for both cytology and HPV testing

Please find our suggested algorithms to guide decision making for HPV testing for primary cervical cancer screening and Cytology with HPV co-testing. Also enclosed is a table of comparison of our available cervical cancer screening products to guide patient decision making.

ASCUS - Atypical Squamous Cells – Undetermined SignificanceCIN – Cervical Intraepithelial Neoplasia

References:

1. Co-testing for detection of high-grade cervical intraepithelial neoplasia and cancer compared with cytology alone: a meta-analysis of randomized controlled trials. Bouchard-Fortier et al, J Public Health (Oxf). 2014 Mar;36(1):46-55. doi: 10.1093/pubmed/fdt057.

2. Primary cervical cancer screening with human papillomavirus: End of study results from the ATHENA study using HPV as the first-line screening test. Wright et al, Gynecol Oncol (2014), http://dx.doi.org/10.1016/j.ygyno.2014.11.076

3. Use of primary high risk human papillomavirus testing for cervical cancer screening: Interim clinical guidance. Huh et al, Gynecol Oncol (2015), http://dx.doi.org/10.1016/j.ygyno.2014.12.022

4. Human papillomavirus testing versus repeat cytology for triage of minor cytological cervical lesions. Arbyn et al, Cochrane Database Syst Rev. 2013 Mar 28;3:CD008054. doi: 10.1002/14651858.CD008054.pub2.

• Seegene HPV PCR uses multiple real time PCR technology to detect and identify 19 high-risk HPV genotypes (including HPV 16 and 18) and 9 low-risk HPV genotypes

• Digene HPV Test uses Hybrid Capture 2 (HC2) technology to test for 13 high-risk HPV genotypes (including HPV 16 and 18) and 5 low-risk genotypes

Disclaimer of Medical LiabilityQuantum Diagnostics Sdn Bhd and the author are not responsible or liable for any advice, course of treatment, diagnosis or any other information, services or products that an individual obtains through this document. This document is not for use in medical emergencies and users should exercise their own clinical judgment in their practice.

Produced by Dr. Tan Shih Yang, Medical Affairssytan@quantumdxs.com

HPV Testing

Cytology - HPV Co-testing

Repeat HPVtesting in 3 years

Positive

Colposcopy

Repeat HPVtesting in 12 months

Triage by Cytology

Triage by HPV Genotyping

Atypical Squamous Cell - Unknown Significance

(ASC-US)

HPV 16/18 PositiveOther HrHPV

Positive

Negative for IntraepithelialLesion or Malignancy

(NILM)

Negative

Routinescreening in

3 years

RepeatCo-testing12 Months Colposcopy

Cyto-veHPV-ve

Cyto-veHPV+ve

Cyto ASC-US/LSILHPV-ve

Cyto ASC-US/LSILHPV+ve

Suggested algorithm for Cytology with HPV Co-testing

Suggested algorithm for HPV testing as Primary Cervical Cancer Screening

TABLE OF COMPARISON: CERVICAL CANCER SCREENING TESTS

Conventional Pap Smear

Method of collection

Collection done with spatula/brush and placed on slide for analysis

Collection done with brush andplaced in preservation solution

for analysis

Self-collection done with Delphi Screener device

and sent for analysis

• Conventional technique – familiar to patient/doctor

Cytology only

RM 70

3 days 10 days

Cytology or HPV (or both)

RM 120 (Cytology alone) RM 400 (HPV PCR alone)

RM 500 (Cytology + HPV PCR)

3 days (Cytology alone), 10 days (including HPV PCR)

Advantages

Disadvantages

Test Type

Recommended Price

Turnaround Time (TAT)

SurePath(Liquid Based Testing)

Delphi Screener (Vaginal Self-sampling) + Digene HPV Test

• Smaller proportion of cells captured resulting in less representative sample

• Collected sample can only be tested for cytology

• High rate of repeat collection due to inadequate samples, air drying artefacts, overlapping material and debris

• More expensive than conventional Pap Smear

• Sample can be used for both cytology and HPV testing – refer algorithms

• Almost all collected cells captured – more representative sample for analysis

• Lower rate of inadequate samples (vs conventional Pap) - less repeat collections

• Minimises air drying artefact, obscuring, overlapping cellular material and debris (common problems with conventional Pap)

• Easier collection for practitioner

• Self-collection – done at patient convenience and does not have to be performed in a clinical setting

• Minimally invasive – does not require speculum insertion

• Collected sample can only be used for HPV testing

HPV only

RM 425