Camelia Davtyan, MD, FACP Clinical Professor of Medicine Director of Women s Health UCLA Comprehensive Health Program

Camelia Davtyan, MD, FACP Clinical Professor of Medicine Director of Women s Health UCLA Comprehensive Health Program A B C D USPSTF recommends the service. There is high certainty that Offer or provide this service. the net benefit is substantial. USPSTF recommends the service. There is high certainty that the Offer or provide this service. net benefit is moderate, or moderate certainty that the net benefit is moderate/substantial. USPSTF recommends selectively offering or providing this service Offer or provide this service for to individual patients based on professional judgment/patient selected patients depending on preferences. There is at least moderate certainty that the net individual circumstances. benefit is small. USPSTF recommends against the service. There is moderate or Discourage the use of this service. high certainty that the service has no net benefit or that the harms outweigh the benefits. I Statement USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms. Evidence is lacking, of poor quality, or conflicting, and the balance of benefits and harms cannot be determined. If the service is offered, patients should understand the uncertainty about the balance of benefits and harms. High Moderate Low The available evidence includes consistent results from well-designed, well-conducted studies in representative primary care populations. These studies assess the effects of the preventive service on health outcomes. This conclusion is unlikely to be affected by the results of future studies. The available evidence is sufficient to determine the effects of the preventive service on health outcomes, but confidence in the estimate is constrained by such factors as: The number, size, or quality of individual studies. Inconsistency of findings across individual studies. Limited generalizability of findings to routine primary care practice. Lack of coherence in the chain of evidence. As more information becomes available, the magnitude or direction of the observed effect could change, and this change may be large enough to alter the conclusion. The available evidence is insufficient to assess effects on health outcomes. Evidence is insufficient because of: The limited number or size of studies. Important flaws in study design or methods. Inconsistency of findings across individual studies. Gaps in the chain of evidence. Findings not generalizable to routine primary care practice. Lack of information on important health outcomes. More information may allow estimation of effects on health outcomes. USPSTF Ann Intern Med 2012 Jun 19;156(12):880-91 ACOG Obstetrics & Gynecology, Volume 127(1), January 2016:185 187 American Cancer Society/American Society for Colposcopy and Cervical Pathology/American Society for Clinical Pathology (ACS/ASCCP/ASCP) CA Cancer J Clin 2012 May;62(3):147-72 Women ages 21-65 : cytology every 3 provides a reasonable balance between benefits and harms Population Women 21-65 yo Women 30-65 yo Women < 21 Women after removal Women >65 with of the cervix (no adequate prior history of high-grade Women < 30 screening and pre-cancer or not at high risk cervical cancer) Cytology more often than every 3 confers little additional benefit HPV testing+ cytology (co-testing) every 5 in women ages 30-65 offers a comparable balance of benefits and harms and can be done if women prefer to extend the screening interval cytology every 3 Recommendation cytology (Pap smear) every 3. Grade: A co-testing (cytology/hpv testing) every 5. Grade: A Do not screen. Do not screen. Do not screen. Do not screen with HPV testing (alone or with cytology) Screening earlier than age 21 regardless of sexual history, leads to more harms than benefits Clinicians and patients should base the decision to end screening on whether the patient meets the criteria for adequate prior testing and appropriate followup

Recommendations based on good and consistent scientific evidence (Level A): Screening should begin at age 21 (exception: women who are infected with HIV) Women aged 21 29: cervical cytology every 3 co-testing should not be performed (most will clear the HPV infection within 8-24 months ) annual screening should not be performed Women aged 30 65 : co-testing with cytology and HPV testing every 5 is preferred cytology every 3 is acceptable (liquid-based and conventional methods both OK) annual screening should not be performed Women older than 65 : stop screening if adequate negative prior screening results and no history of CIN 2 or higher (3 consecutive negative cytology results or 2 consecutive negative co-test results within the previous 10, with the most recent test within the past 5 ) Women who had hysterectomy with removal of the cervix and have never had CIN 2 or higher, cytology screening and HPV testing should not be done Women with any of the following risk factors may require more frequent cervical cancer screening Women who are infected with HIV Women who are immunocompromised (e.g. organ transplants) Women who were exposed to diethylstilbestrol in utero Women previously treated for CIN 2, CIN 3, or cancer Recommendations based on limited and inconsistent scientific evidence (Level B) Women with a history of CIN 2, CIN 3, or adenocarcinoma in situ: continue screening for 20 after spontaneous regression/appropriate management of CIN 2, CIN 3, or adenocarcinoma in situ, even if past age 65 Women who had a total hysterectomy and have a history of cervical cancer or CIN 2 or higher in the past 20 : cytology alone every 3 for 20 after the initial treatment Women 25 and older: FDA-approved primary HPV screening test can be an alternative to cytology ASCUS positive cytology and negative HPV: repeat co-testing in 3 Cytology-negative and HPV-positive co-test in women >30 old: two options 1. Repeat co-testing in 12 months. If ASCUS or higher, or HPV positive, refer for colposcopy. Otherwise, co-test in 3 2. Immediate HPV genotype-specific testing for HPV-16 and HPV-18: positive test result: refer for colposcopy negative test results: repeat co-testing in 12 months Recommendation is based primarily on consensus and expert opinion (Level C) Women who have received the HPV vaccine should be screened according to the same guidelines as women who have not been vaccinated Professional Organization Age to initiate screening Screening interval ACS 2012 21 Age 21-29: cytology alone every 3 Age 30-65: cytology alone every 3 or cytology +HPV every 5 USPSTF 2012 21 Age 21-29: cytology alone every 3 Age 30-65: cytology alone every 3 or cytology +HPV every 5 ACOG 2016 21 Age 21-29: cytology alone every 3 Age 30-65:cytology alone every 3 or cytology+hpv every 5 Age to discontinue screening 65 if no recent abnormal Pap smears and no risk factors 65 if no recent abnormal Pap smears and no risk factors 65 if > 3 consecutive normal Pap smears or >2 consecutive normal Pap+HPV within 10 (most recent within 5 ) and no risk factors Risk factors: history of DES exposure, HIV positive, immunocompromise, previous treatment of a high-grade precancerous lesion or cervical cancer. Screening pelvic examination in adult women: A clinical practice guideline from the American College of Physicians Ann Intern Med 2014 Jul 1;161(1):67-72. ACP recommends against performing screening pelvic examination in asymptomatic, nonpregnant, adult women (strong recommendation, moderate-quality evidence) Indirect evidence that screening pelvic examination does not reduce mortality/morbidity in asymptomatic adult women No studies assessed the benefit of pelvic examination for other gynecologic conditions (asymptomatic pelvic inflammatory disease, benign conditions, or gynecologic cancer other than cervical or ovarian cancer) Low-quality evidence of harms related to screening pelvic examination (fear, anxiety, embarrassment, discomfort) Cervical cancer screening examination should be limited to visual inspection of the cervix and cervical swabs and should not entail a full pelvic examination. ACOG: Screening pelvic examination in adult women Committee on Gynecologic Practice, No. 534, August 2012 (Reaffirmed 2014) Annual pelvic examination of patients 21 of age or older is recommended Pelvic Examination: 1) inspection of the external genitalia, urethral meatus, vaginal introitus, and perianal region 2) speculum examination of the vagina and cervix 3) bimanual examination of the uterus, cervix, and adnexa; when indicated rectovaginal examination should be performed No evidence supports or refutes the annual pelvic examination (speculum and bimanual examination) for the asymptomatic, low-risk patient The decision whether or not to perform a complete pelvic examination for the asymptomatic patient should be a shared decision after a discussion between the patient and her health care provider.

At the time of menopause, all women should be told about the risks and symptoms of endometrial cancer Women should report any unexpected vaginal bleeding or spotting to their doctors Ovarian cancer is the leading cause of death from gynecologic malignancy in the US 22,000 new cases of ovarian cancer annually 14,000 cancer related deaths annually Population Recommendation Risk Assessment Asymptomatic women without known genetic mutations that increase risk for ovarian cancer Do not screen for ovarian cancer. Women with BRCA1 and BRCA2 genetic mutations, Lynch syndrome (hereditary nonpolyposis colon cancer), or a family history of ovarian cancer are at increased risk for ovarian cancer. Women with an increased-risk family history should have genetic counseling/evaluation: 2 or more first- or second-degree relatives with a history of ovarian cancer or a combination of breast and ovarian cancer women of Ashkenazi Jewish descent: 1 first-degree relative or 2 second-degree relatives on the same side of the family with breast or ovarian cancer. Screening Tests Transvaginal ultrasonography and serum cancer antigen (CA) 125 Balance of Benefits Annual screening with transvaginal ultrasonography and serum CA-125 testing in women does not and Harms decrease ovarian cancer mortality. Screening for ovarian cancer can lead to important harms, including major surgical interventions in women who do not have cancer. Harms of screening for ovarian cancer outweigh the benefits. SGO and NCCN (National Comprehensive Cancer Network): screen high risk women every 6 months with CA 125 and TVUS beginning at age 30 35 or 5 10 earlier than the age of affected family member ACOG and NCI (National Cancer Institute): no evidence that screening improves survival in high risk women USPSTF: Ann Intern Med. 2014 Feb 18;160(4):271-81. primary care providers should screen women who have a family history of breast, ovarian, tubal, or peritoneal cancer using a familial risk tool (Ontario Family Health Assessment Tool, Manchester Scoring System, Referral Screening Tool, Pedigree Assessment Tool, FHS-7, etc.) If positive screening result, refer for genetic counseling, with further BRCA testing if warranted. Women without a family history associated with an increased risk for mutations should not receive routine genetic counseling or BRCA testing Screen women whose family history may be associated with an Do not recommend genetic counseling or BRCA testing to increased risk for BRCA mutations and refer for genetic women whose family history is not associated with an counseling and BRCA testing (if indicated after counseling) increased risk for BRCA mutations GRADE D GRADE B High risk breast cancer diagnosis before age 50 bilateral breast cancer family history of breast and ovarian cancer or presence of breast cancer in 1 male family member multiple cases of breast cancer in the family ACOG: genetic risk assessment of women with >20%-25% risk for an inherited predisposition to breast and ovarian cancer ACOG Practice Bulletin No. 103: Hereditary breast and ovarian cancer syndrome. Obstet Gynecol. 2009 Apr. 113 (4):957-66 1 or more family member with 2 primary types of BRCA-related cancer Ashkenazi Jewish ethnicity

Screening Tests Intervention Balance of Benefits and Harms Genetic risk assessment and BRCA mutation testing are generally multistep processes involving identification of women who may be at increased risk for potentially harmful mutations, followed by genetic counseling by suitably trained health care providers and genetic testing of selected high-risk women when indicated Tests for BRCA mutations are highly sensitive and specific for known mutations, but interpretation of results is complex and generally requires posttest counseling earlier, more frequent, or intensive cancer screening risk-reducing medications (e.g., tamoxifen or raloxifene) risk-reducing surgery (e.g., mastectomy or salpingo-oophorectomy) In women whose family history is associated with In women whose family history is not an increased risk for potentially harmful BRCA associated with an increased risk for mutations, the net benefit of genetic testing and potentially harmful BRCA mutations, the early intervention is moderate. net benefit of genetic testing and early intervention ranges from minimal to potentially harmful. Genetic testing should be offered if: An individual has a personal or family history suggestive of an inherited cancer syndrome The genetic test can be adequately interpreted Testing will influence medical management of the patient or other relatives The potential benefits of testing outweigh the potential risks. Second-leading cause of cancer death among women in the United States Population Women aged 40-49 Women aged 50-74 Women aged 75 Recommendation Individualize decision to begin biennial screening according to the patient's circumstances and values. Grade: C Screen every 2. Grade: B No recommendation. Grade: I (Insufficient Evidence) Most frequently diagnosed among women aged 55-64 In 2015 : 232, 000 women were diagnosed with the disease 40, 000 women died of BC (median age of death=68 ) Risk Assessment Screening Tests This recommendation applies to women aged 40 who are not at increased risk by virtue of a known genetic mutation or history of chest radiation. Increasing age is the most important risk factor for most women. Standardization of film mammography has led to improved quality. Timing of Screening Benefits of Benefits and Harms Rationale for No Recommendation (I Statement) Evidence indicates that biennial screening is optimal. A biennial schedule preserves most of the benefit of annual screening and cuts the harms nearly in half. A longer interval may reduce the benefit. There is convincing evidence that screening with film mammography reduces breast cancer mortality, with a greater absolute reduction for women aged 50 to 74 than for younger women. Harms of screening include psychological harms, additional medical visits, imaging, and biopsies in women without cancer, inconvenience due to false-positive screening results, harms of unnecessary treatment, and radiation exposure. False-positive results are a greater concern for younger women; treatment of cancer that would not become clinically apparent during a woman's life (overdiagnosis) is an increasing problem as women age. Among women 75 or older, evidence of benefit is lacking These recommendations apply to asymptomatic women aged >40 No history of breast cancer/high risk breast lesion No high risk for breast cancer because of a genetic mutation (BRCA1 or BRCA2 or other familial breast cancer syndrome) No history of chest radiation at a young age) DBT (digital breast tomosynthesis) as primary screening: insufficient evidence (I recommendation) Adding other methods (ultrasound, MRI) in women with dense breasts and negative mammogram: insufficient evidence (I recommendation) false positive results are common and more frequent in younger women, women with dense breasts (use of DBT may reduce false positives) Biennial screening 50 74 avoids 7 BC deaths Annual screening 50 74 avoids 10 BC deaths and yields 11 more overdiagnoses per 1,000 women screened

Women age 40 49: "C" recommendation is not a recommendation against mammography screening; it signifies moderate certainty of a small net benefit for screening The decision to screen should be an individual one, made after a woman weighs the potential benefit against the possible harms Women with a first degree relative (parent, child, or sibling) with breast cancer may potentially benefit more than average risk women False positives and recommendations for additional imaging (125/1,000) are highest in women 40 49 (Ann Intern Med 2016; 164:226 235) Advances in systemic therapy (Ann Intern Med 2016; 164: 236 243) have not reduced the relative benefits of screening have reduced the absolute benefits because of their positive effect on survival How hard should we try to prevent one death from breast cancer? RR for BC mortality per 10,000 women screened over 10 0.92 for age 39 49; 3 deaths prevented 0.86 for age 50 59; 8 deaths prevented 0.67 for age 60 69; 21 deaths prevented 0.8 for age 70 74; 13 deaths prevented Radiation induced breast cancer incidence and mortality from digital mammography screening Ann Intern Med 2016; 164:205 214 Annual screening of 100,000 women aged 40 74 induces 125 breast cancer cases leading to 16 deaths averts 968 breast cancer cases by early detection Biennial screening started at age 50 reduced the risk of radiation induced cancer 5 folds Women who need more views (large breasts, implants) have a higher risk of radiation induced cancer Recommendations based on limited and inconsistent scientific evidence (Level B): women aged 40 and older should be offered screening mammography annually Recommendations based primarily on consensus and expert opinion (Level C): Clinical breast examination: women aged > 40 annually women aged 20 39 every 1 3. Breast self awareness should be encouraged and can include breast self examination. Women should report any changes in their breasts to their health care providers. Educate women on predictive value of screening mammography potential for false positive results and false negative results potential for additional imaging or biopsies that may be recommended Women with lifetime risk of breast cancer of 20% or greater, based on risk models that rely on family history (such as BRCAPRO, BODACEA, or Claus), but who are either untested or test negative for BRCA gene mutations, can be offered enhanced screening. MRI is not recommended for screening average risk women at average risk Women who test positive for BRCA1 and BRCA2 mutations: Recommend enhanced screening Discuss risk reduction methods Women ages 40 to 44 should have the choice to start annual breast cancer screening with mammograms if they wish to do so Women age 45 to 54 should get annual mammograms Women 55 and older should get mammograms every 2, or have the choice to continue yearly screening When to stop screening: Screening should continue as long as a woman is in good health and is expected to live >10 more All women should be familiar with the benefits, limitations, and potential harms linked to breast cancer screening. They should know how their breasts normally look and feel and report any breast changes to a health care provider Annual MRI and a mammogram starting at age 30 and continued for as long as a woman is in good health (evidence is limited about the best age to start screening shared decision making between patients and their health care providers) Lifetime risk of breast cancer of >20% 25% based on risk assessment tools rely on family history (such as the Claus model) Known BRCA1 or BRCA2 gene mutation First degree relative (parent, brother, sister, or child) with a BRCA1 or BRCA2 gene mutation, and have not had genetic testing History of radiation therapy to the chest between the ages of 10 30 Diagnosis of Li Fraumeni syndrome, Cowden syndrome, Bannayan Riley Ruvalcaba syndrome, or have first degree relatives with one of these syndromes Some women (because of family history, a genetic tendency, or other factors) should be screened with annual MRIs along with mammograms.

There s not enough evidence to make a recommendation for or against yearly MRI screening for women who: Have a moderately increased risk of breast cancer (lifetime risk of 15% to 20%) Have dense breasts ( extremely or heterogeneously dense) on mammogram Gail model bases its risk estimates on certain personal risk factors (current age, age at first menstrual period and history of prior breast biopsies) along with any history of breast cancer in first degree relatives Claus model estimates risk based only on family history of breast cancer in both first and second degree relatives Risk assessment tools (like the Gail model) that are not based mainly on family history are not appropriate to use with the ACS guidelines to decide if a woman should have MRI screening Women at average risk: Yearly screening from age 40: until life expectancy is <5 7 or if abnormal results of screening would not be acted upon (age or comorbid conditions) Women at increased risk: Women with BRCA1 or BRCA2 mutations or women who are untested but have firstdegree relatives (mothers, sisters, or daughters) who have a BRCA mutation: Yearly screening starting by age 30 (but not before age 25) Women with 20% lifetime risk for breast cancer on the basis of family history (both maternal and paternal) and women with mothers or sisters with pre menopausal breast cancer : Yearly starting by age 30 (but not before age 25), or 10 earlier than the age of diagnosis of the youngest affected relative Women with histories of mantle radiation (usually for Hodgkin's disease) between the ages of 10 30: Yearly starting 8 after the radiation therapy, but not before age 25 Women with biopsy proven lobular neoplasia (lobular carcinoma in situ and atypical lobular hyperplasia), atypical ductal hyperplasia (ADH), ductal carcinoma in situ (DCIS), invasive breast cancer or ovarian cancer: Yearly from time of diagnosis