Preventive Oncology

In many respects, cancer is a preventable disease. Estimates indicate that approximately one half of all cancer cases either arise from modifiable risk factors or can be detected as precursor lesions before the development of disease with metastatic potential. ^[1]

Prevention of cancer can take place on several different levels:

• Primary prevention addresses the cause of cancer, so disease does not occur
• Secondary prevention identifies disease before the onset of symptoms and keeps it from becoming more extensive
• Tertiary prevention reduces complications and progression of disease once it has become clinically apparent

At this time, cancer is the second most common cause of death in men and women younger than 85 years in the United States, but is the most common cause of death for Hispanics, Asian-Americans, and Native Americans. Although the number of cancer deaths continues to increase with the aging and growth of the population, age-standardized US death rates from cancer have been decreasing. ^[2] The US cancer death rate peaked at 215.1 per 100,000 population in 1991 and declined to 149.0 per 100,000 population in 2018. The overall incidence rate of cancer in women has slightly increased since 2013, but in men it has remained stable.

These declines have been attributed to risk reduction strategies, detection of early disease, and improvement in treatment strategies. This review addresses the first 2 of those factors, to summarize the evidence for prevention in oncology.

Assessment of an individual's risk is a key step in cancer prevention; risk assessment programs have been developed at many cancer centers to identify people who are at high risk. Review of personal and family medical history, work history, and lifestyle can help identify cancer risk factors, which may be modifiable (eg, tobacco use, sun exposure) or nonmodifiable (eg, family history of cancer, sex, ethnicity, race, advancing age, hormone levels). Combinations of modifiable and nonmodifiable risk factors place some people at particularly high risk for cancer.

Models of cancer risk have been developed to permit calculation of an individual's risk for a specific type of cancer. One of the best known of these is the Gail model, which predicts breast cancer risk on the basis of current age, race, age when menstruation began, age of first live birth, number of close relatives with breast cancer, number of breast biopsies, and the presence or absence of atypical hyperplasia on breast biopsies. ^[3] Like most cancer risk models, the Gail model has limitations: it does not include ovarian cancer history or breast cancer in second-degree relatives such as aunts, cousins, or grandparents. This model may also be less accurate in predicting risk in non-white women. Therefore, risk models should be selected based on each individual's situation in order to calculate risk as accurately as possible.

Overall, approximately 10% of cancers occur because of hereditary predisposition, such as mutations in cancer susceptibility genes (eg, BRCA1 and BRCA2). Many of these mutations can be identified through analysis of a blood or tissue sample. Currently, genetic testing is recommended for individuals who have a personal or family history that is suggestive of an inherited cancer syndrome.

Identification of the appropriate person for testing leads to more informative results for the entire family. In most cases, the person who has had the cancer that best fits the hereditary pattern should be chosen for testing. If a mutation is identified in this individual, others in the family who are at risk can then be tested for that specific mutation. Genetic analysis is ideally preceded by careful genetic counseling, which continues after determination of gene mutation status. Identification of a genetic alteration may change recommendations for cancer screening, chemoprevention, and prophylactic surgery.

In addition to risk from genetic syndromes, it is estimated that approximately another 15-20% of cancers are familial, which may be due to low-penetrance genetic changes or the effects of shared environment and behaviors. The remainder of cancers in the general population are considered sporadic.

Modifiable risk factors for cancer include tobacco use, sun exposure, diet, exercise, obesity, alcohol use, hormone replacement therapy (HRT), environmental/occupational exposures, infectious exposures, and sexual activity.

Tobacco use

Tobacco use accounts for almost one third of cancer deaths in the US. ^[4] Of these, lung cancer is the most common, but cancers of the blood, head and neck, esophagus, liver, pancreas, liver, stomach, cervix, kidney, colon, and bladder have also been linked to smoking. ^[5] Many chemicals are present in tobacco smoke, including at least 69 known carcinogens. ^[6] Smokeless tobacco—chewing tobacco and dipping snuff—contains at least 28 carcinogens. ^[7]

Smoking may also promote more aggressive forms of cancer: for example, tobacco use is associated with higher-grade and higher-stage prostate cancer. ^[8] Secondhand smoke, also known as environmental tobacco smoke, has been associated with both lung and sinus cancers in nonsmokers. ^[9] ln addition, considerable evidence indicates that smokeless tobacco and cigars also have deadly consequences, including lung, laryngeal, esophageal, and oral cancers. ^[7]

Carcinogenesis from tobacco use occurs through several mechanisms, including direct delivery of carcinogens to tissues, inflammation, and breakdown of physiologic barriers. ^[10] Cessation of tobacco use has been shown to reduce both cancer-related and all-cause mortality. Health benefits start soon after quitting and can be seen even in long-time users. ^[11] For former smokers who have been abstinent for 10 years, the risk of lung cancer is one half that of current smokers. This risk falls to as low as 10% for ex-smokers who have quit for 30 years or more. Moreover, the risk for cancers of the mouth, throat, and esophagus lessens significantly 5 years after quitting, and the risk of developing bladder or cervical cancers also decreases after just a few years. ^[12]

Most individuals require several quit attempts before they are able to stop smoking. The addiction to tobacco use is both psychological and biochemical. Medications are available to address the biochemical aspects, whereas counseling and other social support are recommended for treating the psychological aspects.

Nicotine replacement therapy provides nicotine without the other components of tobacco and can be administered through a patch, nasal spray, chewing gum, lozenge, or inhaler. Clinical trials have demonstrated that the use of nicotine replacement doubles the rate of quitting tobacco use. ^[13]

The addition of bupropion (Zyban), an antidepressant medication, may increase the efficacy of nicotine replacement. ^[14] A meta-analysis has also shown that bupropion doubles the quit rate when used as monotherapy. ^[15] However, this medication should be avoided in individuals with a history of seizures or eating disorders.

Another medication for smoking cessation is varenicline (Chantix),which was found to be superior to bupropion in 3 clinical trials. ^{[16, 17, 18]}  Unblinded studies comparing varenicline and nicotine replacement suggested that the quit rates may be higher with varenicline. ^{[19, 20]}  However, a randomized controlled trial that compared 12 weeks of treatment with nicotine patch only (n=241), varenicline only (including 1 pre-quit week; n=424), and nicotine patch + nicotine lozenge (n=421) found no significant differences in carbon monoxide–confirmed rates of smoking abstinence at 26 weeks. ^[21]

Individuals with depression or other neuropsychiatric disorders should not take varenicline, as this medication may exacerbate their symptoms. Both varenicline and bupropion appear to be safe in pregnancy. ^[22]

A randomized controlled trial in 385 1 pack/day smokers found that treatment with bupropion plus varenicline did not appear to increase smoking abstinence rates above that seen with varenicline alone. ^[23]  However, a prospective study concluded that a particular subset of smokers—men with a baseline Fagerstrom Test for Nicotine Dependence (FTND) score ≥ 6 and cigarette consumption ≥ 20/day—benefited substantially from combination therapy with varenicline plus bupropion: after 12 weeks of treatment, the abstinence rate was 71.0% with combination therapy versus 43.8% with varenicline plus placebo. ^[24]

Of course, the ideal way to reduce tobacco-associated cancers is for people to not start using tobacco in the first place. Community programs for youth and public service announcements are two means of addressing this issue.

Sun exposure

Nonmelanoma skin cancers comprise 40% of malignancies in the US. The incidence rates of melanoma, although much lower than that of nonmelanoma skin cancers, are increasing and this condition has a much higher propensity for metastasis and death. ^[2]

Ultraviolet radiation is a well-established carcinogen for both melanoma and nonmelanoma skin cancers. However, the patterns of sunlight exposure associated with these cancers differ significantly. Squamous cell carcinoma tends to occur in those who have chronic sun exposure, often due to occupational exposure from working outdoors. ^{[25, 26]}   Episodes of intense ultraviolet exposure, particularly in children and others without a history of chronic sun exposure, is associated with melanoma incidence, ^[27] and a history of blistering sunburns more than doubles the risk of melanoma. ^[28]  Basal cell carcinoma, although usually associated with chronic sun exposure, has also been linked to intermittent exposure in a significant proportion of cases. ^[29] In addition, the use of tanning beds has been associated with increased skin cancer incidence ^[30] ; in fact, the World Health Organization (WHO) has recommended against the use of these devices for individuals younger than age 18 years. ^[31]

Interest in vitamin D as a chemopreventive agent for several types of cancer has made sun avoidance a controversial topic, because this nutrient is most easily and effectively obtained from sun exposure.  However, at this time, most groups recommend limiting exposure to the sun during peak hours (between 10 AM and 4 PM); using protective clothing, including hats and sunglasses; and using sunscreens with a sun protection factor (SPF) of 30 or greater. Sunscreens should be broad-spectrum and contain agents that work against both ultraviolet (UV) A and UVB radiation.

Nicotinamide has also been shown to have chemopreventive effects for nonmelanoma skin cancer. In a randomized, double-blinded clinical trial in patients with a history of nonmelanoma skin cancers, use of nicotinamide resulted in a 30% decrease in the incidence of squamous cell carcinoma and a 20% decrease in basal cell carcinoma as compared with placebo. ^[32]  

Proper use of sunscreen is also critical: regardless of the SPF, all sunscreen should be applied approximately 15 minutes before sun exposure and then reapplied liberally to all sun-exposed areas of the skin at least every 1.5-2 hours or after swimming or perspiring heavily. A randomized clinical trial demonstrated statistically significant reduction in the incidence of squamous cell carcinoma with regular use of sunscreen; however, it should be noted that this protective effect did not extend to basal cell carcinoma and that the study was underpowered to assess effect on melanoma risk. ^[33]  

Another study of over 1600 patients demonstrated that daily (as compared to discretionary) use of sunscreen resulted in a 50% reduction of melanoma incidence at 10 years and a 73% reduction in invasive melanoma incidence. ^[34]  Several meta-analyses have assessed the effects of sunscreen use on melanoma risk and found no evidence of increased risk. ^{[35, 36, 37]} However, sun avoidance and clothing protection remain the mainstays of skin cancer prevention.

Diet

Multiple components of the diet have been studied, both singly and in combination, for their effects on cancer risk. However, study of diet has proved difficult. Epidemiologic studies may have limited reliability because of inaccurate recall and multiple confounding factors, whereas clinical trials are subject to noncompliance, inappropriate form of the nutrient, or an insufficient follow-up period. ^[38]

Total dietary fat appears to affect the incidence of prostate cancer but has not been consistently proven to affect rates of colon or breast cancer. ^[39] lt should be noted that fat intake is generally evaluated with adjustments for caloric intake and weight gain in order to isolate any effects of the fats themselves. Additional investigation of the effects of types of fat is ongoing. Individuals with high levels of consumption of red meat have been found to have an increased risk of colorectal cancer. ^{[40, 41, 42, 43, 44]}

Some dietary practices appear to reduce cancer risk. The link between fruit and vegetable intake and decreased overall cancer risk is weak ^{[45, 46]} ; however, pooled analyses suggest a 25% reduction in the incidence of distal (but not proximal) colon cancer in those who consumed more than 800 g of fruits and vegetables per day. ^[47] Studies focused on tomato products suggest a benefit for prostate cancer risk, possibly due to the lycopene content in these foods. ^[48]

Consumption of calcium has been associated with a decreased incidence of any cancer in women and a decreased incidence of colon cancers in both men and women. ^[49] Epidemiologic studies have found that increased fiber intake is associated with a decreased risk of colon cancers and adenomas; however, clinical trials of a high-fiber diet showed no effect on the rates of adenoma recurrence. ^{[50, 51, 52, 53]}

Overall dietary recommendations from the American Cancer Society (ACS) include the following ^[54] :

• Eating foods that are high in nutrients, such as a variety of fruits, vegetables, and whole grains, in amounts to achieve and maintain a healthy body weight
• Limiting or eliminating red/processed meats, sugar-containing beverages, highly processed foods, and refined grain products
• Limiting or eliminating consumption of alcohol

Exercise

Estimates indicate that a sedentary lifestyle is responsible for approximately 5% of cancer deaths. ^[55] Higher levels of physical activity have been associated with decreases in the risks of colon and breast cancers; possible decreased risks of endometrial, prostate, liver, pancreatic, stomach, and lung cancers have been described as well. ^{[56, 57, 58, 59, 60, 61, 62]} For colon and breast cancers, the benefit of physical activity has been demonstrated at multiple weight levels, which implies that the effect of the activity is independent of an effect of weight reduction. The mechanism of the protective effect remains uncertain but may be related to effects on immunity, hormone levels, or prostaglandins.

The frequency, duration, or intensity of exercise needed to prevent cancer has not been determined definitively. The American Cancer Society recommends that adults engage in moderate intensity exercise for 150-300 minutes per week, or vigorous exercise for 75-150 minutes per week.. For children, the recommendation is to exercise for at least 60 minutes per day. ^[54]

Obesity

Epidemiologic studies have indicated that excess weight or obesity result in 14% of cancer deaths in men and 20% of cancer deaths in women. ^[63] The cancers associated with obesity are similar to those associated with decreased physical activity. Excess weight has been found to account for 10-40% of colorectal, endometrial, kidney, esophageal, and postmenopausal breast cancers. ^[64]

Possible links have also been described for some hematologic malignancies and cancers of the prostate, liver, gallbladder, pancreas, stomach, ovary, and cervix, as well. Interventions such as bariatric surgery may reduce the risk of cancer deaths by as much as 60%. ^[65]

Alcohol use

Long-term alcohol use has been associated with approximately 4% of incident cancer cases. ^[66] In a study of a large database of women, 1 alcoholic beverage per day increased overall cancer risk by 6%. ^[67] The increase in cancer incidence in this group involved increased risks of cancers of the head and neck, esophagus, rectum, liver, and breast. The Women's Health Study also showed an increase in breast cancer risk associated with moderate alcohol consumption. ^[68]

The mechanism of carcinogenesis associated with alcohol use is not fully understood at this time but may involve inflammatory, epigenetic, hormonal, or metabolic effects. Several of the metabolites of ethanol have been identified as carcinogens. ^[69] The American Cancer Society recommends limiting alcohol use to 2 drinks per day for men and 1 drink per day for women (due to the slower metabolism of alcohol by women). A drink is 12 ounces (oz) of beer, 5 oz of wine, or 1.5 oz of 80-proof liquor. ^[54]

Hormone replacement therapy

Considerable epidemiologic evidence suggests that the duration of a woman's exposure to endogenous estrogen affects breast cancer risk. Support for this hypothesis includes the increased risk of breast cancer for women with an earlier age of menarche, later age of menopause, nulliparity, and later age at first live birth, as well as higher serum estrogen concentrations. For women who take estrogen-­only hormone replacement therapy, meta-analyses of epidemiologic studies indicate a mildly increased risk of breast cancer. ^{[70, 71, 72, 73]}

The primary clinical trial to investigate this question was the Women's Health Initiative trial, in which estrogen-only hormone replacement therapy was not found to increase breast cancer risk when results were reported at a mean follow-up of 7.1 years. ^[74] However, combination therapy with estrogen-progestin hormone replacement did demonstrate a significantly increased risk, with a hazard ratio of 1.2. ^[75] This risk remained elevated for several years after discontinuation of combination therapy but then declined rapidly. ^[76] After the results of the Women's Health Initiative study were made public, a subsequent decline in breast cancer incidence was noted in the US, which has been attributed in part to a decrease in the use of combination hormone replacement. ^[77]

Hormone replacement therapy has been shown to increase breast density, which, in turn, decreases the sensitivity of mammograms. ^{[78, 79]} In the Women's Health Initiative study, postmenopausal women on combination progesterone/estrogen replacement had an average increase of 6% in mammographic density, whereas their counterparts taking placebo had an approximately 1% decrease over the same period. ^[80]

Environmental and occupational exposures

Geographic patterns of cancer incidence may provide insight into cancer etiology. Possible risk factors include environmental exposures and occupational exposures from the air or water.

Workplace exposure to chemicals such as coal-tar–based products, benzene, cadmium, uranium, asbestos, or nickel can significantly increase cancer risk. For example, a significant proportion of bladder cancers may be due to chemical exposures in the aluminum, dye, paint, petroleum, rubber, and textile industries. Occupational exposures to radon and asbestos have been linked to lung cancer, and a small percentage of lung cancers are attributable to air pollution. Arsenic exposure has also been linked to increased incidence of nonmelanoma skin cancers. ^[81]

The International Agency for Research on Cancer (IARC) has conducted extensive evaluations of potential carcinogens based on data from epidemiologic and animal studies. The IARC defines a carcinogenic agent as one capable of increasing the incidence of malignant neoplasms, reducing their latency, or increasing their severity or multiplicity. ^[82] At this time, 121 agents are classified as group 1, or agents that are known to be carcinogenic to humans. Another 89 agents are classified as group 2A, or probable carcinogens in humans. Monographs detailing the evaluations of these agents can be accessed on the IARC website.

Infectious exposures

Approximately 17% of cancers occurring worldwide may be attributed to an infectious etiology. ^[4] The primary cancers with known associations with viral infections include:

• Cervical and anogenital cancers ( human papillomavirus [HPV])
• Hepatocellular carcinoma (HCC) ( hepatitis B [HBV]and C [HCV]) ^{[83, 84]}
• Kaposi sarcoma (human herpes virus [HHV]-8)
• Adult T-cell leukemia ( human T-cell lymphotropic virus -1 [HTLV-I])
• Several types of non-Hodgkin lymphoma ( Epstein-Barr virus and HHV-8). ^[85]

Infection with human immunodeficiency virus (HIV) also increases the risk of Kaposi sarcoma and non­-Hodgkin lymphoma. In some instances, these cancers may be acquired immunodeficiency syndrome (AIDS)–defining malignancies.

Measures to prevent transmission of viral carcinogens include vaccination against carcinogenic types of HPV (see Vaccines and Medical Prevention), use of sterile needles in the healthcare and community (eg, tattoo and drug use) settings, and screening of potential blood donors. The estimated risk of hepatitis infection via blood transfusion is approximately 1 in 58,000 to 269,000 for HBV and 1 in 2 million for HCV. Risk of transmission of HTLV-1 by transfusion is 1 in 2 million, and that of HIV infection by transfusion is approximately 1 in 2 million. ^{[86, 87, 88]}

For individuals who are infected with a virus that has the potential to cause cancer, several interventions are possible. Treatment of HIV infection with highly active antiretroviral therapy (HAART) can prevent lymphomas associated with this virus. ^[89] Similarly, treatment of chronic HBV infection with interferon or nucleotide analogues to reduce the viral load also decreased the incidence of hepatocellular carcinoma. ^[90] Alcohol avoidance may also decrease the development of hepatoma in those with chronic hepatitis.

Bacterial infection with Helicobacter pylori is associated with risk of gastric cancer. Some data suggest that eradication of H pylori infection through regimens of antibiotics and proton pump inhibitors may be effective as primary prevention of gastric cancer. ^{[91, 92, 93]} This approach is currently being evaluated in a large-scale international clinical trial.

Sexual activity

Because some viral carcinogens are transmitted via bodily fluids, increased numbers of sexual partners or sexual contact with infected partners can increase the risk of these cancers, especially in persons with a compromised immune system. Although most women are exposed to HPV in their lifetime, infection is usually transient. When this virus cannot be cleared by the body, cervical cancer may develop. HPV infection (particularly with serotypes 16 and 18) is also linked to anal cancer, especially in individuals with HIV infection. ^[94]

Means of reducing sexual transmission of carcinogenic viruses include awareness of the sexual and medical history of partners and use of barrier methods such as a condom during sexual intercourse.

Breast Cancer Screening

Screening for breast cancer can include different tests, of which clinical breast examination (CBE) and mammography are commonly used.

Breast self-examination

Studies have shown that breast self-examination (BSE) does not affect breast cancer diagnosis, mortality, or stage at diagnosis. ^{[95, 96]} In other studies, however, individuals who performed more thorough examinations did appear to derive a benefit. ^{[97, 98]} The US Preventive Services Task Force (USPSTF) recommends against teaching BSE. ^[99] However, many experts continue to include self-examination in their recommendations due to the low cost and the benefit of making the patient an active participant in her health.

American Cancer Society (ACS) guidelines advise that it is acceptable for women to choose not to do BSE or to do BSE regularly (monthly) or irregularly. Beginning in their early 20s, women should be told about the benefits and limitations of BSE. Whether a woman ever performs BSE, the importance of prompt reporting of any new breast symptoms to a health professional should be emphasized. Women who choose to do BSE should receive instruction and have their technique reviewed on the occasion of a periodic health examination. ^[100]

Clinical breast examination

When performed correctly by trained medical personnel in combination with mammography, clinical breast examination has greater sensitivity but a higher false-positive rate than mammography alone. ^[101] One study suggested, however, that the overall effect on the cost-benefit ratio could be considered detrimental, as 55 false-positive results were identified for every cancer detected by examination that was not detected on mammography. In practice, nonstandardized breast examinations have a sensitivity of about 36% but detect about 5% of cancers not visible on mammograms. ^[102]

Overall, in settings in which mammography is available, clinical breast examination may provide a slight improvement in breast cancer detection. Nevertheless, the ACS does not recommend clinical breast examination for breast cancer screening in average-risk women at any age. ^[100] However, clinical breast examination is a cost-effective measure in countries that do not have access to imaging resources. ^[103]

Mammography

Since 1990, the mortality rate from breast cancer has been declining, although the rate of decline has slowed in recent years. ^[2] A study using several statistical models estimates that use of screening mammograms accounts for 28-65% of that reduction (median, 46%). ^[104] A meta-analysis of randomized controlled trials showed a significant 34% reduction in breast cancer mortality at 7 years in those who had mammographic screening. ^[105] A subsequent review indicated that the survival benefit from mammography was greater in women older than 50 years than in those of age 40 to 49 years. ^[106] However, numerous other studies have demonstrated decreased mortality in women in their 40s as well. ^{[107, 108, 109, 110]}  

Types of mammograms in use include film mammograms and digital mammograms. Images from digital mammograms are electronically captured and stored, whereas those from film mammograms are provided via traditional radiographic films. Overall, cancer detection rates are similar regardless of which type of mammogram is used. ^{[111, 112, 113, 114, 115]} The exceptions to this rule are that digital mammography is more accurate in premenopausal women and in women with dense breasts. ^[116]

Most experts agree that screening mammography should be performed routinely in women between the ages of 50 and 69 years. The frequency of screening in this population has been a controversial issue, however, as has the use of screening in younger women. Guidelines vary in their recommendations on these topics, and place increasing emphasis on patient choice.

For women age 50 to 69 years, some guidelines recommend annual mammography, whereas others advocate biennial or annual examination; Canadian guidelines recommend mammography every 2 to 3 years (weak recommendation). ^{[117, 118, 119]} Data that directly address this question are sparse, but one observational study comparing annual and biennial screening showed no significant disadvantage from the biennial schedule in terms of detection rate or stage at time of diagnosis. ^[120]

For women age 40 to 49, the breast cancer incidence and the sensitivity of mammograms are both lower than they are in women aged 50-69 years. The ACS recommends that average-risk women start annual mammograms at age 45 and consider transitioning to biennial screening at age 55. ^[100]   The American College of Physicians (ACP), the Canadian Task Force on Preventive Health Care, and the Advisory Committee on Cancer Prevention in the European Union advise discussion of screening with patients and shared decision-making.regarding initiation of screening at age 40  ^{[121, 122]   [123]}  The American College of Obstetricians and Gynecologists (ACOG) recommends offering mammography at ages 40 to 49 and, if after counseling the patient desires it, initiating annual or biennial screening. ^[118]   Other groups, such as the USPSTF, recommend against routine mammography in women aged 40-49 years, instead advocating that physicians discuss the risks and benefits of biennial screening with women in this age group. ^[117]   

Data are conflicting in this area: a significant decrease in breast cancer mortality was found on meta-analysis of those who started screening in their 40s ^[106] but not in a larger randomized clinical trial of annual mammography versus usual care. ^[124] A cost-effectiveness study has shown that mammograms cost $21,400 per year of life saved for women aged 50-69 years, whereas the cost was $105,000 per year of life saved for women in their 40s. ^[125] Although the cost for women in their 40s was 5-fold higher, both of these values fall within the accepted range for cost effectiveness.

Recommendations for when to stop mammography also vary. The USPSTF concluded that the current evidence is insufficient to assess the balance of benefits and harms of screening mammography in women aged 75 years or older. ^[117]  ACOG guidelines recommend that whether to continue mammography after age 75 should involve shared decision-making that includes a discussion of the woman’s health status and longevity. ^[118]  The ACS recommends that women continue screening mammography as long as their overall health is good and they have a life expectancy of 10 years or longer. ^[100]

Incorporation of bone mineral density (BMD) into decision-making for breast cancer screening has been suggested for individuals in this 70-79 year age group, as those with higher BMD have an increased risk of breast cancer compared with those with low . ^[126] A general rule that has been suggested for this population is that screening continue for those who have a life expectancy of 10 years or greater.

The false-positive rate of mammography is approximately 11% in the US. ^[127] Risk factors for a false-positive result include younger age, previous breast biopsy, family history of breast cancer, current estrogen use, inconsistent screening, and lack of previous mammograms for comparison. ^[128] Women with a false-positive result on a mammogram will be called back for additional imaging and possible biopsy of a lesion that is ultimately found to be benign.

Overdiagnosis, or screen detection of cancers that would normally not cause clinical morbidity or affect mortality, remains an issue with mammography. Estimates of overdiagnosis range from 1 in 3 to 1 in 6 cancers detected by screening mammogram. ^{[129, 130]}

Some women express concern regarding the radiation associated with regular mammographic screening. Direct data regarding the risk associated with this level of radiation exposure are lacking, but a study of a risk model comparing the risk of radiation and the mortality benefit of mammographic detection concluded that the net effect of mammograms was positive for women older than age 40 years. ^[131]

However, it is important to note that women with BRCA mutations may be more susceptible to the effects of radiation to the breast. Studies of BRCA carriers showed that those with exposure to chest x-rays were 54% more likely to develop breast cancer; this risk increased with multiple x-rays or x-­rays done at an early age. ^[132] In contrast, a study of mammograms in another BRCA population did not find an increased risk of breast cancer in a multivariate model. ^[133]

Breast ultrasonography

In the US, breast ultrasonography is not usually performed as a screening study. The addition of ultrasonography to mammography has been shown to increase sensitivity but decrease specificity. ^{[134, 135, 136]} At present, although ultrasonography remains a tool for diagnosis, it is not a tool for screening of the breast.

Breast magnetic resonance imaging

At this time, breast magnetic resonance imaging (MRI) is not used for routine screening in the general population, and no studies of the effect of screening breast MRI on breast cancer mortality have been published to date. In women at high risk of breast cancer, a comparison of breast MRI and mammography showed that MRI was significantly more sensitive but less specific than mammography. ^{[137, 138, 139, 140]} Women who undergo screening with breast MRI must be made aware of the increased risk of a false-positive result that requires additional studies or a biopsy. ^{[138, 141]}

Guidelines published by the ACS recommend annual breast MRI (usually in addition to annual mammography) for the following patients ^[142] :

• Women who are carriers of mutations in the BRCA genes, or other germline mutation carriers with a known markedly increased risk of breast cancer

• First-degree relatives of mutation carriers who have not been tested themselves

• Women who have a history of radiation to the breast between the ages of 10 and 30 years

• Women with a lifetime risk of breast cancer estimated at 20% or greater according to family history–based risk assessment models (eg, BRCAPro, Myriad, Tyrer-Cuzick).

The ACS guidelines state that additional data are required before making a recommendation for or against screening with breast MRI in those who have a personal history of breast cancer, those with precancerous conditions such as lobular carcinoma in situ (LCIS) or atypical hyperplasia, those with dense breasts, or those who have a 15-20% lifetime risk of breast cancer. MRls are not recommended for those with a lifetime breast cancer risk of less than 15%.

In the United Kingdom, the National Institute for Health and Clinical Excellence (NICE) also issued guidelines for screening with breast MRI. These guidelines suggest annual MRI be done for the following women ^[143] :

• Age 30–49 years who have not had genetic testing but have a greater than 30% probability of being a BRCA carrier
• Age 30–49 years with a known  BRCA1 or  BRCA2 mutation
• Age 20–49 years who have not had genetic testing but have a greater than 30% probability of being a  TP53 carrier
• Age 20–49 years with a known  TP53 mutation. Consideration may also be given to MRI for these women from ages 50-69
• Age 30 to 49 years with a personal history of breast cancer who remain at high risk of breast cancer

Cervical Cancer Screening

The Papanicolaou (Pap) smear is the standard screening test for cervical cancer. HPV is the etiologic agent for most cervical cancers, and HPV testing may be used in combination with Pap smear for screening.

Pap smears

This test consists of sampling and examination of the cells at the transformation zone at the junction between the endocervix and ectocervix, which is the site of cervical dysplasia and cancers.

The efficacy of the Pap smear has never been evaluated in a randomized clinical trial, although an observational study in Canada showed a decrease in cervical and uterine cancer mortality rates in areas with high screening rates by Pap smear; areas with low rates showed an increase in mortality from these cancers. ^[144]

As the use of Pap smears to screen for cervical cancer became implemented internationally, many other countries reported corresponding declines in cervical cancer incidence and mortality. ^{[145, 146, 147, 148, 149, 150, 151, 152]} In addition, a case­-control study found that lack of a Pap smear within the 5 years before a cervical cancer diagnosis conveyed an almost 3-fold increase in risk of invasive cancer. ^[153]

Two methods of Pap smears are in current use: the conventional smear and liquid-based cytology. The performances of these tests are similar for identifying high-grade squamous lesions with the potential to develop into cancer. ^{[154, 155, 156, 157, 158, 159, 160]} Low-grade lesions and atypical squamous or glandular cells are better detected by the liquid-based technique, ^{[161, 162, 163, 164, 165, 166, 167]} and a number of reviews have also found that specimen adequacy is better with the liquid-based cytology, but it is not clear that this result represents a clinically significant benefit. ^{[154, 155, 161, 162, 168]} An additional benefit of the liquid-based testing is that the same specimen may be used for the Pap smear and for HPV testing (see below). Cost and availability of liquid-based testing measures are other factors that figure into the decision of which method to use.

Approximately 6-7% of Pap smears per year are read as abnormal. ^{[169, 170]} Sensitivity and specificity of this test vary substantially: estimates of the sensitivity range from 30% to 87%, whereas specificity is reported as 86-100%. ^[171]

Human papillomavirus testing

Two types of tests have been developed to identify high-risk types of HPV, the etiologic agent for most cervical cancers. The first type identifies whether any of 14 high-risk HPV types are present. Examples of this type of test include the Hybrid Capture 2 and the Cervista HPV HR test. The second test, as exemplified by the Cervista HPV 16/18 test, detects HPV types 16 and 18, which are responsible for the majority of cervical cancers and high-grade cervical lesions.

HPV testing has been studied alone and in conjunction with Pap smears. This test does have a greater sensitivity than cervical cytology alone; however, its specificity is lower. ^{[172, 173, 174, 175, 176, 177]}

Recent changes in guidelines from the American Cancer Society now recommend primary HPV testing as the preferred measure for women over the age of 25. ^[178]  Although current ACS guidelines do include provisions for cervical cytology alone and in combination with HPV testing, these are included with the understanding that future guidelines will not include these options as primary HPV testing becomes available in all settings.

Guideline recommendations

Guidelines for cervical cancer screening are available from the USPSTF, the ACS, amongst other groups; however, in November 2021, the USPSTF announced a public comment period that could change their recommendations in this area. Currently, the USPSTF and ACOG recommend starting Pap smears at age 21 years, whereas the ACS recommends starting at age 25. ^{[178, 179, 180]}  Although previous guidelines recommended that screening start 3 years after the onset of sexual activity, sexual history is not a consideration in current guidelines.

The ACS recommends that women have primary HPV testing every 5 years from age 25-65. Alternatives would be HPV and cytology every 5 years, or cytology alone every 3 years. ^[178]

The USPSTF currently recommends cytology alone every three years from ages 21-29. For women 30-65 years old, screening with cytology alone every 3 years, high-risk HPV testing every 5 years, or combination cytology and HPV co-testing every 5 years is preferred. ^[179]

The USPSTF advises stopping screening at age 65 years, in women who have had adequate prior screening and are not otherwise at high risk for cervical cancer. The ACS recommends that in women older than 65, screening can be discontinued after either three consecutive negative cytology tests or two negative cytology and HPV tests within 10 years, provided the most recent test was within 5 years.

Women who have undergone total hysterectomy (with removal of the cervix) for benign causes do not need cervical screening; however, those who have a history of cervical or uterine cancer should continue to have routine age-based screening for at least 20 years. Individuals with a history of immunosuppression or diethylstilbestrol (DES) exposure in utero may also require more frequent screening.

Colorectal Cancer Screening

Colorectal cancer screening can be performed using a variety of methods; there are a total of 6 testing options recommended by the Multi-Society Task Force, which includes representation from the ACS, the American College of Radiology, and the US Multi-Society Task Force on Colorectal Cancer. ^[181]  The screening modalities for colon cancer can be classified into two general categories: stool-based tests and endoscopic or radiologic examinations. 

Stool-based tests

Stool-based tests have the ability to detect early cancers and may detect advanced adenomas. The first of these tests, the guaiac-based fecal occult blood test (gFOBT), has been shown in clinical trials to reduce colon cancer mortality by up to 33% when done on an annual basis. ^{[182, 183, 184, 185, 186]} Advantages of this test include its low cost and noninvasive method. However, the specificity of the gFOBT is low, giving the potential for many false-positive results that require additional testing, such as colonoscopy. Patients should avoid nonsteroidal anti-inflammatory drugs (NSAIDs), red meat, and high doses of vitamin C (> 250 mg) for 48 hours before and during the testing period, and samples should be collected from 3 consecutive stools.

More recently, immunochemical-based FOBTs (also known as fecal immunochemical tests [FIT]) and the stool DNA panel have also become available. The cost of the immunochemical test is greater than that of the guaiac-based test, but the specificity may be higher. Stool DNA panels are also expensive and require a greater quantity of stool to perform the test. The suggested screening interval is every 1-3 years for stool DNA and annually for FIT.

Endoscopic and radiographic tests

Studies that image the colon and rectum have the potential to detect not only cancers but adenomatous polyps that may develop into cancers. Endoscopic tests such as flexible sigmoidoscopy and colonoscopy have been in use as screening tools for many years. Although clinical trials have not addressed the effect of these endoscopic modalities on colorectal cancer mortality in the general population, observational studies have shown that flexible sigmoidoscopy may significantly reduce deaths from colorectal cancers that occur in the area visualized by this scope. ^{[187, 188, 189]}

The major limitation of flexible sigmoidoscopy is that it visualizes only the distal 60 cm of the colon. Abnormal results require examination of the entire colon by colonoscopy. The recommended screening interval for flexible sigmoidoscopy is every 5 years. Colonoscopy, however, requires significant bowel preparation and carries the risk of complications such as bleeding or bowel perforation. If there is no evidence of polyps, colonoscopy is repeated every 10 years for screening.

Computed tomography (CT) colonography, formerly referred to as "virtual colonoscopy," has been a more recent development. Similar to optical colonoscopy, this modality visualizes the entire bowel and requires a bowel preparation; however, CT colonography does not pose the risks of complications associated with optical colonoscopy. Positive results require colonoscopy to obtain a biopsy. There is also a risk associated with the cumulative radiation exposure for this test, which could become significant if it is performed regularly for screening. CT colonography should be performed every 5 years. Colon capsule studies have also been approved by the FDA for individuals who are unable to undergo colonoscopy or FIT.

Guideline recommendations

Several different groups have produced guidelines for colorectal cancer screening. All of the tests listed above are endorsed by the Multi-Society Task Force (MSTF). ^{[190, 181, 191]}  This group encourages physicians and patients to discuss the screening options in terms of early detection (stool-based tests) or prevention (radiographic or endoscopic tests), and then to select a test within the chosen category. The MSTF, ACS, and American College of Gastroenterology (ACG) all indicate that colonoscopy every 10 years or FIT testing annually are the preferred means of screening. The ACG and the MSTF also suggest colon capsule as an alternative means of screening for those who cannot do the preferred tests: however, the ACS does not include colon capsule in its recommendations at this time.

In 2018 the ACS recommended that colorectal screening begin at age 45 in persons at average risk, in part because of data showing an increase in colorectal cancer in younger populations. ^[192]  The USPSTF and Multi-Society Task Force have also updated their guidelines to reflect a starting age of 45. ^{[181, 193]}  The guidelines recommend continuing screening to age 75, and individualized consideration of screening between ages 75 and 85.

Individuals who are at increased risk of colon cancer due to a personal history of polyps, inflammatory bowel disease (IBD), or previous colorectal cancer or a family history of colorectal cancer should have screening by colonoscopy. The age at which screening is initiated may also be earlier for these individuals, based on the youngest age at which a family member was diagnosed with colorectal cancer or the time of onset of symptoms from inflammatory bowel disease. The examinations should be performed more frequently in these individuals as well, with annual colonoscopy recommended for those at genetic risk and colonoscopy every 1-3 years for those with inflammatory bowel disease.

For individuals with a first-degree relative with colorectal cancer but no evidence of a genetic syndrome, screening should start at age 40 years (or 10 years prior to the earliest age of cancer diagnosis) and be repeated every 5 years. For those with a second-degree relative with colon cancer, the starting age should be 45-50, and the interval may be every 10 years if there are no concerning findings. ^[194]

Individuals with a personal history of adenoma should have repeat colonoscopy 3-5 years after the polyp has been removed, with the interval determined on the basis of the histology and number of polyps identified. For very large polyps that may not have been completely resected, short-term repeat colonoscopy several months later may be appropriate. Subsequent intervals for colonoscopy should be 5-10 years in individuals with polyps. For those with a personal history of colon cancer, colonoscopy should be repeated 1 year after cancer diagnosis, then in 1-3 years (based on findings at the 1-year colonoscopy). If no further pathology is identified, colonoscopy should continue at intervals of no more than 5 years for subsequent screening. ^{[195, 194]}

Endometrial Cancer Screening

Studies of endometrial cancer screening are lacking; however, on the basis of expert opinion, this screening is not recommended for the general population. ^[196] Cervical cytology is not sensitive enough to be a reliable screening test for endometrial cancer, although it is effective in detecting pathology of the squamous cells of the cervix, ^{[197, 198, 199, 200, 201]} and endometrial biopsy is an invasive procedure that often does not result in an adequate specimen. In addition, the benefit from presymptomatic diagnosis of endometrial cancer is unclear, as the majority of cancers present as dysfunctional uterine bleeding (DUB) and are diagnosed while still confined to the uterus (stage I).

Women who are at increased hereditary risk of endometrial cancer from Lynch syndrome (hereditary nonpolyposis colorectal cancer [HNPCC]) or from Cowden syndrome may consider undergoing annual endometrial biopsy starting at age 35 years. ^[196] Transvaginal ultrasonography has also been suggested as a consideration for this group, although some evidence suggests that this procedure is not effective in early detection of cancers. ^[202]

Lung Cancer Screening

Guidelines on lung cancer screening have been issued by the ACS, the American College of Chest Physicians (ACCP), and the USPSTF. ^{[203, 204, 205]} The guidelines are in agreement that annual screening with low-dose computed tomography (LDCT) scanning should be offered to patients aged 55 to 74 years who have at least a 30 pack-year smoking history and either continue to smoke or have quit within the past 15 years. Other groups, such as the National Comprehensive Cancer Network (NCCN) recommend initiation of screening at age 50 for those who have at least a 20 pack year history of tobacco use. ^[206]  The guidelines also agree that the shared decision making is required and should include a discussion of benefits and risks.

Ovarian Cancer Screening

Detection of early-stage ovarian cancer has proved difficult: unfortunately, three quarters of ovarian cancers show spread beyond the ovary at the time of diagnosis. Although current guidelines do not recommend screening for ovarian cancer for women in the general population, ^{[207, 208, 209]} screening tests such as the serum biomarker CA125 and transvaginal ultrasonography are frequently used in combination to monitor women who are at increased risk of ovarian cancer due to genetic mutations in BRCA or mismatch repair genes. ^[208]

Serum CA125 levels have fair sensitivity for advanced ovarian cancer but poor specificity. ^[210] A small proportion of healthy women have elevated CA125 levels, and these levels can also be affected by age, smoking status, the menstrual cycle, endometriosis, cirrhosis, fibroids, pelvic inflammatory disease (PID), pleural or peritoneal fluid, or other types of cancers. ^{[211, 212, 213, 214, 215, 216, 217]} A change in CA125 level over time may be a more effective means of assessing for ovarian neoplasms.

A panel of serum proteins, including CA125, was marketed in the US as a screening test for ovarian cancer under the brand name OvaSure. However, this test was designed for a population that had a much higher prevalence of ovarian cancer than that of the general population in the US. ^[218] Concerns about the validity of this test in the general population led to its removal from the market.

The main imaging modality that has been evaluated for ovarian cancer screening is transvaginal ultrasonography. Although its specificity is good, the sensitivity of screening with this modality varies significantly based on the experience of the operator. ^{[210, 219, 220]} Clinical trials to determine whether transvaginal ultrasonography can diagnose early stages of ovarian cancer have had conflicting results. In the National Ovarian Cancer Early Detection Program, all cancers detected in high-risk women were stage III. ^[221] However, other studies conducted in lower-risk populations did have a significant proportion of early disease among the cancers detected. ^{[222, 223, 224]}

Because of the higher prevalence of ovarian cancer in women at high risk, the predictive value of screening is higher in this population; therefore, some expert groups do endorse screening of high-risk women. However, the National Comprehensive Cancer Network (NCCN) advises that current data do not support routine ovarian cancer screening; transvaginal ultrasound has not been shown to be sufficiently sensitive or specific, but may be considered at the clinician’s discretion starting at age 30–35 y, and similar caveats apply to serum CA-125 testing. ^[225]

Prostate Cancer Screening

The mainstays of prostate cancer screening are measurement of prostate-specific antigen (PSA) and digital rectal examination (DRE). PSA testing originated as a tumor marker to assess recurrence or disease progression for men with a history of prostate cancer; however, it was adopted for screening in the general population before this use was evaluated in randomized trials. Later studies had mixed results: the European Randomized Study of Screening for Prostate Cancer (ERSPC) found a survival benefit associated with PSA screening, whereas the Prostate, Lung, Colorectal, and Ovarian (PLCO) study did not find a benefit associated with screening by PSA and digital rectal examination. ^{[226, 227]} Measurement of PSA can be affected by factors other than prostate cancer, including the following ^{[228, 229, 230]} :

• Benign prostatic hypertrophy (BPH)
• Ejaculation
• Bacterial prostatitis
• Urinary retention
• Use of medications such as 5-alpha reductase inhibitors

Prostate biopsy has also been shown to cause significant elevations in PSA sustained for up to 1 month, whereas digital rectal examination is not felt to have a substantive effect on PSA measurements. ^{[231, 232]} Overall, when abnormal PSA values are defined as those over 4.0 ng/mL, the sensitivity of the PSA test is 70-80% and the specificity is 60-70%. ^[233] A noteworthy exception is the Prostate Cancer Prevention Trial, which showed a sensitivity of only 21% for PSA at this level. ^[234]

Several approaches have been taken to try to improve the utility of PSA measurement, including use of PSA velocity to assess change over time, PSA density to adjust values according to prostate volume as measured by ultrasonography or MRI, the ratio of free to total PSA, and complexed PSA, as well as individualized reference ranges based on age or race. However, these modified values have not replaced standard PSA testing in most practices.

Despite the long-standing use of digital examination of the prostate through the rectum (ie, digital rectal examination), there have been no controlled studies that demonstrated an effect of this test on prostate cancer mortality or incidence. ^[235] Assessment of the prostate by this technique often results in inconsistent results, even among specialists. ^[236] The sensitivity has been estimated at 59% and the specificity at 94%. ^[237] Clinically, the overall sensitivity is improved when digital rectal examination and PSA are used in combination, although PSA appears to outperform digital rectal examination in some aspects. ^{[196, 238, 239]}

Guidelines regarding screening for prostate cancer with PSA testing and digital rectal examination vary considerably. Several groups, including the ACS and the American Urological Association (AUA), recommend discussion of the risks and benefits of screening with the patient and individualizing decisions. ^{[240, 241]}  The USPSTF recommends against screening for prostate cancer unless this discussion is had and the patient expresses a preference for treatment. ^[242]  

For men at average risk, the ACS recommends consideration of starting screening at age 50 years, while the AUA recommends considering starting at age 55 years. For men who are at increased risk of prostate cancer due to family history or ethnic background, the ACS recommends starting at age 45 years (if African-American or with one first-degree relative with prostate cancer prior to the age of 65) or age 40 years (if more than one first-degree relative with prostate cancer). The regimen consists of annual PSA testing, with digital rectal examination optional.

The USPSTF recommends stopping screening at age 70, as does the AUA. The ACS recommends stopping prostate cancer screening if anticipated life expectancy is 10 years or less.

If screening does not detect cancer, the ACS recommends that the time between subsequent screenings depend on the results of the PSA level, as follows ^[240] :

• PSA < 2.5 ng/ml – Retesting may be done every 2 years
• PSA ≥ 2.5 ng/ml – Retesting should be done annually

Other groups, including the Canadian Task Force on Preventive Health Care, and the European Union, find the evidence insufficient to support PSA-based screening. ^{[122, 243, 244]}

Breast Cancer

At present, four medications are available for the primary prevention of breast cancer. Tamoxifen and raloxifene are selective estrogen receptor modulators (SERMs) that have both estrogen agonist and antagonist effects. Exemestane and anastrozole are aromatase inhibitors.

Tamoxifen

The Breast Cancer Prevention Trial (BCPT) found that, compared with patients receiving placebo, tamoxifen users had a 50% reduction in the incidence of invasive and noninvasive estrogen receptor–positive breast cancers. The investigators evaluated the use of tamoxifen for the prevention of breast cancer in women at increased risk based on age older than 60 years, personal history of lobular carcinoma in situ, or a 5-year Gail score of more than 1.66%. ^[245] On long-­term follow-up, the protective effect of tamoxifen persisted, with approximately 43% reduction in invasive cancer risk. ^[246] However, tamoxifen was also shown to produce an approximately 2-fold increased risk of endometrial cancer and thromboembolic events, including stroke.

A second study, the International Breast Cancer Intervention Study (IBIS-l), also found a significant reduction in the incidence of breast cancer in tamoxifen users, but the all-cause mortality rate was higher in the tamoxifen intervention group. ^[247] A meta-analysis concluded that use of tamoxifen reduced breast cancer risk by 38% and doubled the risk of endometrial cancer and thromboembolic events, but it did not affect overall mortality. ^[248]

The USPSTF does not recommend use of tamoxifen for chemoprevention of breast cancer in women of average risk. For those who have an increased risk due to family history, BRCA or other mutation carrier status, or conditions such as lobular carcinoma in situ, the benefits of treatment must be balanced against the risks of side effects on an individual basis. ^[249]

Raloxifene

In the study of tamoxifen and raloxifene (STAR) trial, in which raloxifene (Evista) was compared with tamoxifen for prevention of breast cancer in postmenopausal women, the incidence rates for invasive breast cancer were similar with both drugs, but the risks of thromboembolic adverse effects and endometrial cancer were significantly lower with raloxifene. ^[250] In addition, although the rate of noninvasive breast cancer was higher in the raloxifene group than in the tamoxifen group, this difference did not achieve statistical significance. The profile of other side effects also differed between the 2 groups: tamoxifen was associated with higher rates of gynecologic problems, vasomotor symptoms, and bladder symptoms, whereas sexual dysfunction, musculoskeletal issues, and weight gain were more frequent with raloxifene. ^[251]

The US Food and Drug Administration (FDA) approved raloxifene for use for breast cancer chemoprevention in postmenopausal women. It is important to note that this drug has not been studied in premenopausal women and is not approved for use in this population. To date, there are no reports on the use of raloxifene in BRCA mutation carriers.

Aromatase Inhibitors

Exemestane and anastrozole have been investigated in breast cancer risk reduction in postmenopausal women at increased risk of breast cancer.  A double-blind, placebo-controlled study randomized 3864 women at increased risk of breast cancer to anastrozole 1 mg daily or matched placebo. ^[252]  After a median followup of 5 years, breast cancer incidence was 2% in the anastrozole group and 4% in the placebo group (HR 0.47; 95% CI 0·32-0·68, P < 0·0001). Few side effects were associated with treatment. However, there was no significant difference in all-cause mortality between the groups. 

Similarly, a study of exemestane in 4560 postmenopausal woman at increased risk of breast cancer showed a 65% relative reduction in invasive breast cancer incidence with mean followup of 35 months, as compared with placebo (HR 0.35; 95% CI, 0.18 to 0.70; P=0.002). ^[253] Minimal differences in quality of life were seen between the groups, and no significant difference was noted in mortality.

Although exemestane and anastrozole are not approved by the FDA for breast cancer chemoprevention at this time, they are included for consideration for breast cancer risk reduction for postmenopausal women in guidelines such as those of the National Comprehensive Cancer Network. ^[254]  It should be noted that the aromatase inhibitors were not studied specifically in individuals known to have genetic risk of breast cancer, and the benefit is considered unknown in this population. 

Cancers caused by human papillomavirus infection

Human papillomavirus (HPV) is a common virus that infects epithelial tissue. More than 120 HPV types have been identified. Most HPV types infect cutaneous epithelial cells and cause common warts (eg, those that occur on the hands and feet). Approximately 40 HPV types infect mucosal epithelial cells on the genitals, mouth, and throat.

Most HPV infections are asymptomatic and resolve spontaneously or become undetectable, but some HPV infections can persist and lead to cancer. Persistent infections with oncogenic HPV types can cause cancers of the anus, cervix, penis, vulva, vagina, and oropharynx. The most common oncogenic HPV types are 16 and 18, which are associated with 70% of cervical cancers and 90% of genital warts. ^[255] An estimated 17,600 women and 9,300 men are diagnosed annually in the United States with a cancer caused by HPV. ^[256]

Earlier HPV vaccines—Cervarix, which covered two viral types, and Gardasil, which covered four types—were discontinued in the United States in October 2016. The currently available HPV vaccine, Gardasil 9, covers nine HPV types. The FDA-approved indications for Gardasil 9 are shown in Table 1, below.

Table 1. HPV Vaccine (Open Table in a new window)

Dosage regimens

The nine-valent HPV vaccine is given in either 3 doses over a 6-month period or, in young adolescents, 2 doses over a 6- to 12-month period (see Table 2). The vaccine has been shown to be very effective in the prevention of cervical intraepithelial neoplasia (CIN) grade 2/3 in subjects who had not been previously exposed to HPV. However, the vaccine did not show strong efficacy in preventing premalignant or malignant cervical disease in subjects who were not HPV-naive; nor did the vaccine show efficacy in the treatment of existing HPV infections. ^{[255, 257]}

The Recommended Adult Immunization Schedule, United States, 2020 indicates that all adults to the age of 26 should undergo vaccination for HPV. ^[258]  If the initial dose is given at or after the age of 15, a 3-dose regimen is recommended. If the initial dose is given between the ages of 9 and 14 but only one dose has been given or two doses were given less than 5 months apart, an additional dose is recommended. If the initial dose is given between the ages of 9 and 14 and doses were given at least 5 months apart, no further vaccination is recommended. For individuals between the ages of 27 and 45, a 2-dose or 3-dose course can be considered. 

Adverse effects

The most frequent adverse effect associated with vaccination was a mild reaction at the injection site. ^{[255, 257]} Postlicensure surveillance reports for Gardasil also indicated increased risk of post­vaccination syncope and thromboembolic events; however, nearly all thromboembolic events occurred in those with a known risk factor, such as oral contraceptive use or family history of thromboembolic disease. ^[259]

Recommendations

Because cervical cancers can be caused by HPV genotypes other than those contained in the vaccines, cervical screening should be continued after vaccination. In addition, the duration of protection against HPV after vaccination remains unknown.

Several groups have made recommendations regarding the appropriate use of HPV vaccinations. The Advisory Committee on Immunization Practices (ACIP) and the American Cancer Society advise routine vaccination for boys and girls at age 11-12 years. ^{[256, 260]} The American College of Obstetricians and Gynecologists recommends that vaccination should be offered to girls before their becoming sexually active (at age 13-15 years). ^[261]  The WHO recommends vaccinations for girls between the ages of 9 and 13 years. ^[262]  

All groups advocate "catch-up" vaccination for children and young adults between the ages of 13 and 26 years if they have not had previous vaccination, and they indicate that vaccination may occur as early as age 9 years, particularly with children who have a history of sexual abuse or assault. HPV testing is not recommended before vaccination. Additionally, adults not previously vaccinated should be educated about the benefit of the vaccine. The 9-valent HPV vaccine is indicated for males and females aged 9 through 45 years. ^[263]

Immunosuppressed/immunocompromised individuals

HPV vaccination has been recommended for immunocompromised individuals up to the age of 26. A three-dose schedule may be used. Overall, however, data remain lacking in this area.

Prostate Cancer

5-alpha reductase inhibitors have been shown to have protective effects against prostate cancer in clinical trials. Meta-analysis of 5-alpha reductase inhibitor studies indicates that these agents decrease the risk of prostate cancer by approximately 25%. ^[264]

Finasteride

The Prostate Cancer Prevention Trial (PCPT), which compared finasteride to placebo in nearly 19,000 men who were at increased risk of prostate cancer due to age, ethnic background, or family history of prostate cancer, was closed early due to a 25% decrease in numbers of prostate cancer in the finasteride group relative to the control group. However, the finasteride group was noted to have more aggressive cancers (Gleason score > 6). ^[265]

Several possible explanations for this result have been presented, including diagnostic bias due to decreased prostate volume in the participants taking finasteride and detection bias due to the effects of finasteride on PSA test results. ^{[266, 267, 268, 269, 270, 271]} Finasteride decreases PSA levels by 50% on average. ^{[272, 273, 274]}

Side effects included gynecomastia and sexual dysfunction, which was mild and decreased over time. It remains unclear whether finasteride decreases mortality from prostate cancer.

Dutasteride

The REDUCE (REduction by DUtasteride of prostate Cancer Events) trial, which investigated dutasteride, another 5-alpha reductase inhibitor, as a chemopreventive agent for men at increased risk of prostate cancer showed a 23% decrease in prostate cancer incidence in the dutasteride arm, which achieved statistical significance. ^[275] Unlike the PCPT trial, the incidence of high-grade cancers was not increased in the REDUCE study. No differences in overall or prostate-specific mortality were seen between the two groups.

Recommendations

Guidelines from the American Society of Clinical Oncology and the American Urologic Association recommend that men discuss the risks and benefits of chemoprevention with these medications with their physicians. ^[276]

For individuals at very high risk of cancer, such as those with hereditary genetic predisposition, surgical intervention provides another means of risk reduction. Main examples of surgical management of cancer risk include prophylactic mastectomy in BRCA mutation carriers, prophylactic salpingo-­oophorectomy in BRCA carriers and mismatch repair gene mutation carriers, and prophylactic colectomy in individuals with familial adenomatous polyposis (FAP).

Prophylactic mastectomy

Prophylactic mastectomy has been a mainstay of management of BRCA mutation carriers because of their markedly increased risk of breast cancer. Updates to the guidelines from the National Comprehensive Cancer Network have led to consideration of prophylactic mastectomy for women with CDH1, PALB2, PTEN, and TP53 mutations as well as those with BRCA1 or BRCA2 mutations. ^[277]  The breast cancer risk reduction associated with bilateral prophylactic mastectomy is approximately 90%. ^{[278, 279, 280, 281, 282]} Simple or skin-sparing mastectomy techniques are preferred over subcutaneous mastectomy, because the latter technique tends to leave more residual breast tissue with the potential to develop cancer. ^{[283, 284, 285]}

Despite the considerable risk reduction associated with this procedure, utilization of prophylactic mastectomy remains far less than that of prophylactic salpingo-oophorectomy. Possible reasons for the discrepancy between the rates of these prophylactic surgeries include lack of data proving survival benefit, concerns about appearance and sexuality following mastectomy, availability of medications that reduce breast cancer risk, and the options of screening modalities that can detect breast cancer at a premalignant or early stage.

Prophylactic salpingo-oophorectomy

Prophylactic salpingo-oophorectomy has primarily been studied in women with BRCA1 or BRCA2 germline mutations, although it is also appropriate for women with Lynch syndrome (hereditary non­polyposis colorectal cancer) and some other hereditary syndromes. This procedure provides premenopausal BRCA mutation carriers with protection from both ovarian cancer (90-95% risk reduction) and breast cancer (50% risk reduction); for postmenopausal carriers, it provides protection from ovarian cancer only. ^{[286, 287, 288, 289, 290]} Even after oophorectomy, however, a small risk of primary peritoneal cancer remains. ^{[291, 292]}

Prophylactic gynecologic surgery has been shown to improve overall and cancer-related survival in this population. ^[293] Similarly, risk-reducing surgery dramatically decreases the incidence of cancer in the Lynch syndrome population as well. ^[294]

For BRCA mutation carriers, experts recommend that bilateral salingo-oophorectomy take place between the ages of 35 and 40 years or after childbearing is complete. The fallopian tubes should be removed as well, due to the increased incidence of fallopian tube carcinoma in this population. Careful pathology review of both the ovaries and fallopian tubes is vital to detect clinically occult cancers, which is reported in approximately 4-8% of women undergoing this procedure. ^{[295, 296, 297]}

Prophylactic hysterectomy at the time of oophorectomy remains a point of some debate. For women with Lynch syndrome, the risk of endometrial cancer is also increased, and it is appropriate to remove the uterus at the time of oophorectomy. Although BRCA mutations are not generally felt to increase the risk of endometrial cancer, some data suggest that the incidence of these cancers is higher than would be expected in this population. ^{[298, 299]} These results may be due to use of tamoxifen for chemoprevention of breast cancer. Removal of the uterus could allow for more complete removal of the fallopian tubes and as well as use of unopposed estrogen for hormone replacement therapy.

Another issue of debate is the use of hormone replacement therapy after prophylactic oophorectomy, which remains controversial in this population due to the risks of breast cancer. At least one report has found that short-term use of hormone replacement to treat menopausal symptoms after oophorectomy in BRCA carriers did not increase the incidence of cancers. ^[300] However, long-term follow-up data are lacking, so careful counseling regarding the risks and benefits of hormone replacement therapy is appropriate.

Colectomy

Individuals with the hereditary syndrome familial adenomatous polyposis are often afflicted with hundreds to thousands of colorectal polyps and have a virtual certainty of developing colorectal cancer in their lifetime if their disease is unchecked. A standard risk-reducing measure in this population is prophylactic colectomy, which is generally undertaken in known mutation carriers when adenomas cannot be effectively controlled endoscopically. Depending on the phenotype of the individual and other affected members of the family, surgical options include total proctocolectomy with ileal pouch and anastomosis, total abdominal colectomy with ileorectal anastomosis, or total proctocolectomy with ileostomy. For individuals who have an intact rectum after surgery, regular lower endoscopic surveillance is still recommended; similarly, surveillance of the ileal pouch should occur every 2 years in individuals who have undergone this surgical option. ^{[301, 302]}

Although the burden of cancer is daunting, primary and secondary prevention of this disease is possible in many instances. Recent trends for decreased cancer incidence and mortality in the US are due in part to improvements in risk reduction measures and early detection of cancer through screening.