Innersense Voice 139 Jan 15, 2013 Screen to Prevent: Cervical & Prostate Cancer

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1 Screening test to detect cancer at its earliest stage has been one of the most studied areas in our fight against cancer. However, the benefits of screening in terms of cancer prevention, early detection and subsequent treatment must be weighed against any harm. The success of any screening programme lies in screening tests that are effective, safe, well-tolerated with acceptably low rates of false positive and false negative results. If signs of cancer are detected, more definitive and invasive diagnostic tests are performed to confirm a screen positive result. In this voice we focus on Cervical and Prostate cancer screening. Cervical cancer Cancer of the cervix uteri is the second most common cancer among women worldwide, with an estimated 529,409 new cases and 274,883 deaths in About 86% of the cases occur in developing countries, representing 13% of female cancers. Worldwide, mortality rates of cervical cancer are substantially lower than incidence with a ratio of mortality to incidence to 52% (IARC, GLOBOCAN 2008). The majority of cases are squamous cell carcinoma and adenocarcinomas are less common. (Vaccine 2006, Vaccine 2008, IARC Monographs 2007) India has a population of millions women aged 15 years and older who are at risk of developing cervical cancer. Some 20 % of the global burden of cervical cancer falls on India ( Latest estimates indicate that every year women are diagnosed with cervical cancer and die from the disease. Cervical cancer ranks as the 1st most frequent cancer among women in India, and the 1st most frequent cancer among women between 15 and 44 years of age. About 7.9% of women in the general population are estimated to harbour cervical HPV infection at a given time, and 82.5% of invasive cervical cancers are attributed to HPVs 16 or 18. (IARC, GLOBOCAN 2008) In India, there are no national guidelines available for screening of Cervical Cancer. However, some western European countries and the USA have screening recommendations updated on a routine basis through the work of professional associations or the governments. Current Cervical Cancer Screening Recommendations Population USPSTF ACS/ASCCP/ASCP Younger than 21 years Recommends against screening. Women should not be screened regardless of the age of sexual initiation or other risk factors years Recommends screening with cytology every 3 years. Screening with cytology alone every 3 years is recommended years Recommends screening with cytology every 3 years or for women who want to lengthen the screening interval, screening with a combination of cytology and HPV testing every 5 years. Screening with cytology and HPV testing ( co-testing ) every 5 years (preferred) or cytology alone every 3 years (acceptable) is recommended. Older than 65 years Recommends against screening women who have had adequate prior screening and are not otherwise at high risk for cervical cancer. Women with evidence of adequate negative prior screening and no history of CIN2+ within the last 20 years should not be screened. Screening should not be resumed for any reason, even if a woman reports having a new sexual partner. After hysterectomy Recommends against screening in women who have had a hysterectomy with removal of the cervix and who do not have a history of a high- Women of any age following a hysterectomy with removal of the cervix who have no history of CIN2+ should not be screened for vaginal cancer. Evidence of adequate

2 grade precancerous lesion (ie, CIN 2 or 3) or cervical cancer. negative prior screening is not required. Screening should not be resumed for any reason, including if a woman reports having a new sexual partner. HPV vaccinated Women who have been vaccinated should continue to be screened. Recommended screening practices should not change on the basis of HPV vaccination status. * USPSTF, U.S. Preventive Services Task Force; ACS/ASCCP/ASCP, American Cancer Society/American Society for Colposcopy and Cervical Pathology; ASCP, American Society for Clinical Pathology; HPV, human papillomavirus; CIN, cervical intraepithelial neoplasia. Screening of Cervical Cancer The role of the Pap smear is to screen for cervical cancers and cervical pre-cancers. In its early stages, cervical cancer usually has no symptoms. To diagnose cervical cancer, the following procedures are followed: Pap smear With advent of Liquid Based Cytology the methodology of doing a Pap smear examination has changed. Liquid based cytology brought down the no. of equivocal reports due to inadequate sample or slide and also provided the opportunity to keep the sample for preparing the smear again and have a relook. This further enabled to have HPV testing from same sample. LBC compared to conventional Pap smear Agreement in approx. 90% LBC normal 93.5% of conventional PAP normal; 6.5% upgraded (cervical atypia, LGL, HGL, cervical cancer) LBC improved sensitivity from 68 to 78 % LBC improved specificity from 79 to 86 % LBC tends to be more sensitive and specific than conventional smears in detecting dysplasia. Also, addition of HPV DNA co-testing increased sensitivity to 100% Abnormal results are grouped as follows: ASCUS or AGUS LSIL (low-grade dysplasia) or HSIL (high-grade dysplasia) Carcinoma in situ (CIS) Atypical squamous cells (ASC H) Atypical glandular cells (AGC) Presence of atypical cells of uncertain significance. The changes may be due to HPV. Precancerous changes are likely to be present, hence the greater risk of cervical cancer. Abnormal changes are likely to lead to cervical cancer. Abnormal changes have been found and may be HSIL. Cell changes that may lead to cancer are seen in the upper part of the cervical canal or inside the uterus. HPV Testing HPV research in Cervical Cancer and subsequent development of molecular tests for detecting it in cervical swabs have ushered in a new age in cancer screening. Almost all guidelines that are available worldwide state the importance of HPV screening in cervical cancer screening. Molecular techniques available for HPV detection can be broadly divided into those technologies that are not amplified, such as nucleic acid probe tests, and those that utilize amplification, such as polymerase chain reaction (PCR). Amplification techniques can be further divided into three separate categories: (1) target amplification, in which the assay amplifies the target nucleic acids (for example, PCR); (2) signal amplification, in which the signal generated from each probe is increased by a compound-probe or branched-probe technology; and (3) probe amplification, in which the probe molecule itself is amplified (for example, ligase chain reaction).[1]

3 Digene HC2 High-Risk HPV DNA Test- The digene HC2 High-Risk HPV DNA Test is an in vitro nucleic acid hybridization assay of QIAGEN with signal amplification and chemiluminescence for the qualitative detection of 13 types of HPV in cervical specimens. It employs specific RNA probes, hybridization, antibody capture, and signal amplification. QIAGEN s digene HPV Test has an excellent clinical sensitivity of up to 100% in primary adjunctive screening when combined with a Pap smear test. Cervista HPV HR test for HPV detection- Cervista TM HPV HR test is an vitro diagnostic test which uses Invader chemistry, a signal amplification method involving two types of isothermal reactions: one occurs on target DNA and other as fluorescent signal generation. The test, unlike others, has an inbuilt internal control and has role in qualitative detection of DNA from 14 high-risk HPV types. It has 100% CIN3 Detection in ASC-US: 95% CI (85.1% - 100%) and 99.1% negative predictive value (NPV) for CIN2+. (Cervista HPV multicenter clinical trial, ) HPV DNA detection & Subtyping- HPV DNA test is a rapid and sensitive method for screening of HPV infection in genital specimens. This PCR based method detects HPV DNA independent of its subtype. A Genetic Analyzer can then be used for subtyping of HPV. The advantage of DNA sequencing is that it can detect all available subtypes of HPV. All these molecular methods offered scope for rapid screening with simultaneous detection if high risk subtypes and hastened implementation of HPV detection in Cervical Cancer New developments in cervical cancer research and treatment New ways to prevent and treat cancer of the cervix are being researched. Some of the promising new developments include the following:[2] A new approach: mrna-based detection of E6/E7 oncoproteins Many recent publications have shown that, following the integration of the HPV genome into the host genome in cervical cells, persistent expression of viral oncoproteins E6 and E7 occurs. This persistent expression initiates the cervical cancer process by affecting the cell cycle leading to cell proliferation and making them early cancer markers. Infact, E6/E7 mrnabased methods have been found to be more specific for the detection of precancerous lesions (CIN2+) in women with ASCUS/LSIL cytology than DNA-based methods, leading to improved triage of women with ASCUS/LSIL cytology. (J. Med. Virol.2004; 73:65-70.) Available from: HPV vaccines Vaccines have been developed to prevent infection with some of the HPV types associated with cervical cancer. Two HPV vaccines are currently on the market: Gardasil (Merck & Co.) and Cervarix (GlaxoSmithKline). Gardasil is supposed to protect against HPV types, 6, 11, 16 & 18, on the other hand Ceravix protects against HPV types 16 & 18. Both vaccines have been shown to prevent potentially precancerous lesions of the cervix. However, most world medical bodies still recommend screening even in vaccinated individuals. Drug treatment of pre-cancers Standard treatment of cervical pre-cancer (such as CIN) includes cryotherapy, laser treatment, and conization. Recent studies to see if medicines can be used instead have had some promising results. In one study, patients with CIN2 or CIN3 took a drug called diindolylmethane (DIM) for 12 weeks. Follow-up testing showed improvement - in some women, the CIN went away completely. In another study, CIN was treated by applying a drug called cidofovir to the cervix. In more than half of the treated women, the CIN resolved completely. More studies are needed before this can become a standard treatment. Prostate cancer Prostate cancer is the second most frequently diagnosed cancer of men ( new cases, 13.6% of the total) and the fifth most common cancer overall. Nearly three-quarters of the registered cases occur in developed countries ( cases). Incidence rates of prostate cancer vary by more than 25-fold worldwide, the highest rates are in Australia/New Zealand (104.2 per 100,000), Western and Northern Europe, Northern America, largely because largely because the practice of prostate specific antigen (PSA) testing and subsequent biopsy has become widespread in those regions.the lowest agestandardised incidence rate is estimated in South- Central Asia (4.1 per 100,000). With an estimated deaths in 2008, prostate

4 cancer is the sixth leading cause of death from cancer in men (6.1% of the total). [GLOBOCAN 2008 (IARC), Section of Cancer Information (2/1/2013)] A study conducted on Cancer incidence rates among South Asians in four geographic regions: India, Singapore, UK and US by Tanuja Rastogi et al observed the lowest total cancer incidence rates in India (111 per among males, age-standardized to the 1960 world population) and the highest among US whites (362 and 296). American Cancer Society recommendations for prostate cancer early detection The American Cancer Society (ACS) recommends that men have a chance to make an informed decision with their health care provider about whether to be screened for prostate cancer. The decision should be made after getting information about the uncertainties, risks, and potential benefits of prostate cancer screening. Men should not be screened unless they have received this information. Assuming no prostate cancer is found as a result of screening, the time between future screenings depends on the results of the PSA blood test: Men who choose to be tested who have a PSA of less than 2.5 ng/ml, may only need to be retested every 2 years. Screening should be done yearly for men whose PSA level is 2.5 ng/ml or higher. Because prostate cancer often grows slowly, men without symptoms of prostate cancer who do not have a 10- year life expectancy should not be offered testing since they are not likely to benefit. Overall health status, and not age alone, is important when making decisions about screening. Even after a decision about testing has been made, the discussion about the pros and cons of testing should be repeated as new information about the benefits and risks of testing becomes available. Further discussions are also needed to take into account changes in the patient's health, values, and preferences. SCREENING RECOMMENDATIONS At age 50 for men who are at average risk of prostate cancer and are expected to live at least 10 more years. At age 45 for men at high risk of developing prostate cancer which includes African Americans and men who have a first-degree relative (father, brother, or son) diagnosed with prostate cancer at an early age (younger than age 65). at age 40 for men at even higher risk (those with more than one first-degree relative who had prostate cancer at an early age). Screening Tools for Prostate Cancer [3] PSA - The PSA blood test looks for the presence in the blood of a protein that is produced specifically by prostate cells called Prostate Specific Antigen (PSA). The percentage of measured prostate-specific antigen (PSA) existing in the free form (free:total PSA ratio) is useful in assessing the risk of prostate cancer in patients with borderline or moderately increased total PSA ( ng/ml) and has been used to help select men who should have follow-up prostate biopsy. The rate of change in PSA levels, referred to as PSA velocity, suggest that men with a PSA velocity that exceeds a certain threshold (0.35 ng/ml per year) should consider having a needle biopsy, even if their overall PSA levels are below the standard cut-off for the procedure and they have a normal result on a digital rectal examination (DRE). Methods being studied include: Free versus total PSA PSA density of the transition zone Age-specific PSA reference ranges PSA velocity and PSA doubling time The amount of PSA in the blood that is free (not bound to other proteins) divided by the total amount of PSA (free plus bound). Evidence suggests that a lower proportion of free PSA may be associated with more aggressive cancer. Blood level of PSA divided by the volume of the transition zone of the prostate. Some evidence suggests that this measure may be more accurate at detecting prostate cancer than the standard PSA test. Age-specific PSA reference ranges may increase the accuracy of PSA tests because a man s PSA level tends to increase with age PSA velocity is the rate of change in a man s PSA level over time, expressed as ng/ml per year. PSA doubling time is the period of time over which a man s PSA level doubles. Evidence suggests that the

5 rate of increase in a man s PSA level may be helpful in predicting whether he has prostate cancer. New developments PCA3 - It is a prostate specific, nonprotein coding RNA that is significantly over expressed in prostate cancer, without any correlation to prostatic volume and/or other prostatic diseases (e.g. prostatitis). It can now easily be measured in urine with a novel transcription-mediated amplification based test. Quantification of PCA3 mrna levels can predict the outcome of prostatic biopsies with a higher specificity rate in comparison to PSA. Several studies have demonstrated that PCA3 can be used as a prognostic marker of prostate cancer, especially in conjunction with other predictive markers. Novel PCA3-based nomograms have already been introduced into clinical practice.it is probably the best adjunct to serum PSA for predicting biopsy outcome, and has proven its clinical relevance by surpassing the predictive abilities of traditional serum biomarkers. Prostate cancer vaccines - Several types of vaccines for boosting the body's immune response to prostate cancer cells are being tested in clinical trials. Unlike vaccines against infections like measles or mumps, these vaccines are designed to help treat, not prevent, prostate cancer. One possible advantage of these types of treatments is that they seem to have very limited side effects. An example of this type of vaccine is sipuleucel-t (Provenge), which has received FDA approval. Another prostate cancer vaccine (PROSTVAC-VF) uses a virus that has been genetically modified to contain prostate-specific antigen (PSA). The patient's immune system should respond to the virus and begin to recognize and destroy cancer cells containing PSA. Early results with this vaccine have been promising. Angiogenesis inhibitors - Growth of prostate cancer tumors depends on growth of new blood vessels (angiogenesis) to nourish the cancer cells. Looking at angiogenesis in prostate cancer specimens may help predict treatment outcomes. Cancers that stimulate many new vessels to grow are harder to treat and have a poorer outlook. Tests offered at SRL Test Name Method Test Code THINPREP CYTOLOGY LIQUID BASED CYTOLOGY 1284 HPV DNA DETECTOR POLYMERASE CHAIN REACTION 1820 HPV DUO (HPV DNA Detector & PAP Smear) POLYMERASE CHAIN REACTION / CYTOLOGY 1821 HPV: HYBRID CAPTURE 2 HIGH RISK HPV DNA TEST DIGENE DNA HYBRID CAPTURE 1823 HUMAN PAPILLOMA VIRUS HIGH RISK INVADER CHEMISTRY, CERVISTA RD1413 PAP SMEAR ABNORMAL REFLEX HPV DETECTION(DNA DETECTOR) CYTOLOGY/POLYMERASE CHAIN REACTION 9216RFX PAP DUO + HYBRID Digene DNA Hybrid Capture and CYTOLOGY 1479 PAP DUO-LIQUIPREP CYTOLOGY [SEMI-AUTOMATION] + HPV-PCR CYTOLOGY+PCR 1822 PAP STAIN CYTOLOGY 1272 PAP STAIN [PHOTO] CYTOLOGY 1272P PROSTATE SPECIFIC ANTIGEN (PSA) [PHOTO] IMMUNOHISTOCHEMISTRY Z041K PROSTATE SPECIFIC ANTIGEN (PSA) FREE & TOTAL CHEMILUMINESCENCE 3547 PROSTATE SPECIFIC ANTIGEN (PSA) TOTAL CHEMILUMINESCENCE 3546 PROSTATE SPECIFIC ANTIGEN, FREE CHEMILUMINESCENCE 3545 PSA REFLEX TO FREE PSA (If PSA is > 4.0, Free PSA performed) CHEMILUMINESCENCE 3548 References 1. Hariri S, Unger ER, Sternberg M, et al. Prevalence of genital human papillomavirus among females in the United States, the National Health and Nutrition Examination Survey, Journal of Infectious Diseases 2011; 204(4): Im SS, Monk BJ Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of California, Irvine Medical Center; Chao Family Comprehensive Cancer Center, 101 The City Drive, Building 23, Room 107, Orange, CA 92868, USA. 3. Jhingran A, Eifel PJ, Wharton JT, et al. Neoplasms of the cervix. In: Kufe DW, Pollock RE, Weichselbaum RR, Bast RC, Gansler TS, Holland JF, Frei E. Cancer Medicine 6. Hamilton, Ontario: BC Decker; Jhingran A, Russel AH, Seiden MV, Duska LR, et al. Cancers of the cervix, vagina and vulva. In: Abeloff MD, Armitage JO, Lichter AS, et al. Clinical Oncology. 4th ed. Philadelphia, Pa; Elsevier; 2008: Antonarakis ES, Eisenberger MA. Expanding treatment options for metastatic prostate cancer. N Engl J Med May 26;364: Andreas Bourdoumis, Athanasios G. Papatsoris, Michael Chrisofos, Eleni Efstathiou, Andreas Skolarikos, Charalambos Deliveliotis University Department of Urology (AB, AGP, MC, AS, CD), Sismanoglio Hospital, Athens, Greece and University Department of Clinical Therapeutics (EE), Alexandra Hospital, Athens, Greece. The Novel Prostate Cancer Antigen 3 (PCA3) Biomarker