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InternalMed_Harrison. Because the aromatase inhibitors are even more effective than tamoxifen in adjuvant breast cancer therapy, it has been hypothesized that they would be more effective in breast cancer prevention. A randomized, placebo-controlled trial of exemestane reported a 65% relative reduction (from 5.5 to 1.9 per 1000 women) in the incidence of invasive breast cancer in women at elevated risk after a median follow-up of about 3 years. Common adverse effects included arthralgias, hot flashes, fatigue, and insomnia. No trial has directly compared aromatase inhibitors with selective estrogen receptor modulators for breast cancer chemoprevention.


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InternalMed_Harrison. Finasteride and dutasteride are 5-α-reductase inhibitors. They inhibit conversion of testosterone to dihydrotestosterone (DHT), a potent stimulator of prostate cell proliferation. The Prostate Cancer Prevention Trial (PCPT) randomly assigned men age 55 years or older at average risk of prostate cancer to finasteride or placebo. All men in the trial were being regularly screened with prostate-specific antigen (PSA) levels and digital rectal examination. After 7 years of therapy, the incidence of prostate cancer was 18.4% in the finasteride arm, compared with 24.4% in the placebo arm, a statistically significant difference. However, the finasteride group had more patients with tumors of Gleason score 7 and higher compared with the placebo arm (6.4 vs 5.1%). Reassuringly, long-term (10–15 years) follow-up did not reveal any statistically significant differences in overall mortality between all men in the finasteride and placebo arms or in men diagnosed with prostate cancer; differences


InternalMed_Harrison

InternalMed_Harrison. follow-up did not reveal any statistically significant differences in overall mortality between all men in the finasteride and placebo arms or in men diagnosed with prostate cancer; differences in prostate cancer in favor of finasteride persisted.


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InternalMed_Harrison. Dutasteride has also been evaluated as a preventive agent for prostate cancer. The Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial was a randomized double-blind trial in which approximately 8200 men with an elevated PSA (2.5–10 ng/mL for men age 50–60 years and 3–10 ng/mL for men age 60 years or older) and negative prostate biopsy on enrollment received daily 0.5 mg of dutasteride or placebo. The trial found a statistically significant 23% relative risk reduction in the incidence of biopsy-detected prostate cancer in the dutasteride arm at 4 years of treatment (659 cases vs 858 cases, respectively). Overall, across years 1 through 4, there was no difference between the arms in the number of tumors with a Gleason score of 7 to 10; however, during years 3 and 4, there was a statistically significant difference in tumors with Gleason score of 8 to 10 in the dutasteride arm (12 tumors vs 1 tumor, respectively).


InternalMed_Harrison

InternalMed_Harrison. The clinical importance of the apparent increased incidence of higher-grade tumors in the 5-α-reductase inhibitor arms of these trials is controversial. It may likely represent an increased sensitivity of PSA and digital rectal exam for high-grade tumors in men receiving these agents. The FDA has analyzed both trials, and it determined that the use of a 5-α-reductase inhibitor for prostate cancer chemoprevention would result in one additional high-grade (Gleason score 8 to 10) prostate cancer for every three to four lower-grade (Gleason score <6) tumors averted. Although it acknowledged that detection bias may have accounted for the finding, it stated that it could not conclusively dismiss a causative role for 5-α-reductase inhibitors. These agents are therefore not FDA-approved for prostate cancer prevention.


InternalMed_Harrison

InternalMed_Harrison. Because all men in both the PCPT and REDUCE trials were being screened and because screening approximately doubles the rate of prostate cancer, it is not known if finasteride or dutasteride decreases the risk of prostate cancer in men who are not being screened. Several favorable laboratory and observational studies led to the formal evaluation of selenium and α-tocopherol (vitamin E) as potential prostate cancer preventives. The Selenium and Vitamin E Cancer Prevention Trial (SELECT) assigned 35,533 men to receive 200 μg/d selenium, 400 IU/d α-tocopherol, selenium plus vitamin E, or placebo. After a median follow-up of 7 years, a trend toward an increased risk of developing prostate cancer was observed for those men taking vitamin E alone as compared to the placebo arm (hazard ratio 1.17; 95% confidence interval, 1.004–1.36).


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InternalMed_Harrison. A number of infectious agents cause cancer. Hepatitis B and C are linked to liver cancer; some HPV strains are linked to cervical, anal, and head and neck cancer; and Helicobacter pylori is associated with gastric adenocarcinoma and gastric lymphoma. Vaccines to protect against these agents may reduce the risk of their associated cancers. The hepatitis B vaccine is effective in preventing hepatitis and hepatomas due to chronic hepatitis B infection.


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InternalMed_Harrison. A quadrivalent HPV vaccine (covering HPV strains 6, 11, 16, and 18) and a bivalent vaccine (covering HPV strains 16 and 18) are available for use in the United States. HPV types 16 and 18 cause cervical and anal cancer; reduction in these HPV types could prevent >70% of cervical cancers worldwide. HPV types 6 and 11 cause genital papillomas. For individuals not previously infected with these HPV strains, the vaccines demonstrate high efficacy in preventing persistent strain-specific HPV infections; however, the trials and substudies that evaluated the vaccines’ ability to prevent cervical and anal cancer relied on surrogate outcome measures (cervical or anal intraepithelial neoplasia [CIN/AIN] I, II, and III), and the degree of durability of the immune response beyond 5 years is not currently known. The vaccines do not appear to impact preexisting infections and the efficacy appears to


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InternalMed_Harrison. Prevention and Early Detection of Cancer be markedly lower for populations that had previously been exposed to vaccine-specific HPV strains. The vaccine is recommended in the United States for females and males age 9–26 years. Some organs in some individuals are at such high risk of developing cancer that surgical removal of the organ at risk may be considered. Women with severe cervical dysplasia are treated with laser or loop electrosurgical excision or conization and occasionally even hysterectomy. Colectomy is used to prevent colon cancer in patients with familial polyposis or ulcerative colitis.


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InternalMed_Harrison. Prophylactic bilateral mastectomy may be chosen for breast cancer prevention among women with genetic predisposition to breast cancer. In a prospective series of 139 women with BRCA1 and BRCA2 mutations, 76 chose to undergo prophylactic mastectomy and 63 chose close surveillance. At 3 years, no cases of breast cancer had been diagnosed in those opting for surgery, but eight patients in the surveillance group had developed breast cancer. A larger (n = 639) retrospective cohort study reported that three patients developed breast cancer after prophylactic mastectomy compared with an expected incidence of 30–53 cases: a 90–94% reduction in breast cancer risk. Postmastectomy breast cancer–related deaths were reduced by 81–94% for high-risk women compared with sister controls and by 100% for moderate-risk women when compared with expected rates.


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InternalMed_Harrison. Prophylactic oophorectomy may also be employed for the prevention of ovarian and breast cancers among high-risk women. A prospective cohort study evaluating the outcomes of BRCA mutation carriers demonstrated a statistically significant association between prophylactic oophorectomy and a reduced incidence of ovarian or primary peritoneal cancer (36% relative risk reduction, or a 4.5% absolute difference). Studies of prophylactic oophorectomy for prevention of breast cancer in women with genetic mutations have shown relative risk reductions of approximately 50%; the risk reduction may be greatest for women having the procedure at younger (i.e., <50 years) ages.


InternalMed_Harrison

InternalMed_Harrison. All of the evidence concerning the use of prophylactic mastectomy and oophorectomy for prevention of breast and ovarian cancer in high-risk women has been observational in nature; such studies are prone to a variety of biases, including case selection bias, family relationships between patients and controls, and inadequate information about hormone use. Thus, they may give an overestimate of the magnitude of benefit. Screening is a means of detecting disease early in asymptomatic individuals, with the goal of decreasing morbidity and mortality. While screening can potentially reduce disease-specific deaths and has been shown to do so in cervical, colon, lung, and breast cancer, it is also subject to a number of biases that can suggest a benefit when actually there is none. Biases can even mask net harm. Early detection does not in itself confer benefit. Cause-specific mortality, rather than survival after diagnosis, is the preferred endpoint (see below).


InternalMed_Harrison

InternalMed_Harrison. Because screening is done on asymptomatic, healthy persons, it should offer substantial likelihood of benefit that outweighs harm. Screening tests and their appropriate use should be carefully evaluated before their use is widely encouraged in screening programs, as a matter of public policy.


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InternalMed_Harrison. A large and increasing number of genetic mutations and nucleotide polymorphisms have been associated with an increased risk of cancer. Testing for these genetic mutations could in theory define a high-risk population. However, most of the identified mutations have very low penetrance and individually provide minimal predictive accuracy. The ability to predict the development of a particular cancer may some day present therapeutic options as well as ethical dilemmas. It may eventually allow for early intervention to prevent a cancer or limit its severity. People at high risk may be ideal candidates for chemoprevention and screening; however, efficacy of these interventions in the high-risk population should be investigated. Currently, persons at high risk for a particular cancer can engage in intensive screening. While this course is clinically reasonable, it is not known if it reduces mortality in these populations.


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InternalMed_Harrison. Sensitivity The proportion of persons with the condition who test positive: a /(a + c) Specificity The proportion of persons without the condition who test negative: d /(b + d) Positive predictive value The proportion of persons with a positive test who (PPV) have the condition: a /(a + b) Negative predictive The proportion of persons with a negative test value who do not have the condition: d /(c + d) Prevalence, sensitivity, and specificity determine PPV aFor diseases of low prevalence, such as cancer, poor specificity has a dramatic adverse effect on PPV such that only a small fraction of positive tests are true positives.


InternalMed_Harrison

InternalMed_Harrison. The Accuracy of Screening A screening test’s accuracy or ability to discriminate disease is described by four indices: sensitivity, specificity, positive predictive value, and negative predictive value (Table 100-2). Sensitivity, also called the true-positive rate, is the proportion of persons with the disease who test positive in the screen (i.e., the ability of the test to detect disease when it is present). Specificity, or 1 minus the false-positive rate, is the proportion of persons who do not have the disease that test negative in the screening test (i.e., the ability of a test to correctly identify that the disease is not present). The positive predictive value is the proportion of persons who test positive that actually have the disease. Similarly, negative predictive value is the proportion testing negative that do not have the disease. The sensitivity and specificity of a test are independent of the underlying prevalence (or risk) of the disease in the population screened,


InternalMed_Harrison

InternalMed_Harrison. proportion testing negative that do not have the disease. The sensitivity and specificity of a test are independent of the underlying prevalence (or risk) of the disease in the population screened, but the predictive values depend strongly on the prevalence of the disease.


InternalMed_Harrison

InternalMed_Harrison. Screening is most beneficial, efficient, and economical when the target disease is common in the population being screened. Specificity is at least as important to the ultimate feasibility and success of a screening test as sensitivity. Potential Biases of Screening Tests Common biases of screening are lead time, length-biased sampling, and selection. These biases can make a screening test seem beneficial when actually it is not (or even causes net harm). Whether beneficial or not, screening can create the false impression of an epidemic by increasing the number of cancers diagnosed. It can also produce a shift in the proportion of patients diagnosed at an early stage and inflate survival statistics without reducing mortality (i.e., the number of deaths from a given cancer relative to the number of those at risk for the cancer). In such a case, the apparent duration of survival (measured from date of diagnosis) increases without lives being saved or life expectancy changed.


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InternalMed_Harrison. Lead-time bias occurs whether or not a test influences the natural history of the disease; the patient is merely diagnosed at an earlier date. Survival appears increased even if life is not really prolonged. The screening test only prolongs the time the subject is aware of the disease and spends as a patient.


InternalMed_Harrison

InternalMed_Harrison. Length-biased sampling occurs because screening tests generally can more easily detect slow-growing, less aggressive cancers than fast-growing cancers. Cancers diagnosed due to the onset of symptoms between scheduled screenings are on average more aggressive, and treatment outcomes are not as favorable. An extreme form of length bias sampling is termed overdiagnosis, the detection of “pseudo disease.” The reservoir of some undetected slow-growing tumors is large. Many of these tumors fulfill the histologic criteria of cancer but will 480 never become clinically significant or cause death. This problem is compounded by the fact that the most common cancers appear most frequently at ages when competing causes of death are more frequent. Selection bias must be considered in assessing the results of any screening effort. The population most likely to seek screening may differ from the general population to which the screening test might be applied. In general, volunteers for studies are


InternalMed_Harrison

InternalMed_Harrison. of any screening effort. The population most likely to seek screening may differ from the general population to which the screening test might be applied. In general, volunteers for studies are more health conscious and likely to have a better prognosis or lower mortality rate, irrespective of the screening result. This is termed the healthy volunteer effect.


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InternalMed_Harrison. Potential Drawbacks of Screening Risks associated with screening include harm caused by the screening intervention itself, harm due to the further investigation of persons with positive tests (both true and false positives), and harm from the treatment of persons with a true-positive result, whether or not life is extended by treatment (e.g., even if a screening test reduces relative cause-specific mortality by 20–30%, 70–80% of those diagnosed still go on to die of the target cancer). The diagnosis and treatment of cancers that would never have caused medical problems can lead to the harm of unnecessary treatment and give patients the anxiety of a cancer diagnosis. The psychosocial impact of cancer screening can also be substantial when applied to the entire population.


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InternalMed_Harrison. Assessment of Screening Tests Good clinical trial design can offset some biases of screening and demonstrate the relative risks and benefits of a screening test. A randomized controlled screening trial with cause-specific mortality as the endpoint provides the strongest support for a screening intervention. Overall mortality should also be reported to detect an adverse effect of screening and treatment on other disease outcomes (e.g., cardiovascular disease). In a randomized trial, two like populations are randomly established. One is given the usual standard of care (which may be no screening at all) and the other receives the screening intervention being assessed. The two populations are compared over time. Efficacy for the population studied is established when the group receiving the screening test has a better cause-specific mortality rate than the control group. Studies showing a reduction in the incidence of advanced-stage disease, improved survival, or a stage shift are weaker


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InternalMed_Harrison. test has a better cause-specific mortality rate than the control group. Studies showing a reduction in the incidence of advanced-stage disease, improved survival, or a stage shift are weaker (and possibly misleading) evidence of benefit. These latter criteria are early indicators but not sufficient to establish the value of a screening test.


InternalMed_Harrison

InternalMed_Harrison. Although a randomized, controlled screening trial provides the strongest evidence to support a screening test, it is not perfect. Unless the trial is population-based, it does not remove the question of generalizability to the target population. Screening trials generally involve thousands of persons and last for years. Less definitive study designs are therefore often used to estimate the effectiveness of screening practices. However, every nonrandomized study design is subject to strong confounders. In descending order of strength, evidence may also be derived from the findings of internally controlled trials using intervention allocation methods other than randomization (e.g., allocation by birth date, date of clinic visit); the findings of analytic observational studies; or the results of multiple time series studies with or without the intervention.


InternalMed_Harrison

InternalMed_Harrison. Screening for Specific Cancers Screening for cervical, colon, and breast cancer is beneficial for certain age groups. Depending on age and smoking history, lung cancer screening can also be beneficial in specific settings. Special surveillance of those at high risk for a specific cancer because of a family history or a genetic risk factor may be prudent, but few studies have assessed the influence on mortality. A number of organizations have considered whether or not to endorse routine use of certain screening tests. Because these groups have not used the same criteria to judge whether a screening test should be endorsed, they have arrived at different recommendations. The American Cancer Society (ACS) and the U.S. Preventive Services Task Force (USPSTF) publish screening guidelines (Table 100-3); the American Academy of Family Practitioners (AAFP) generally follow/ endorse the USPSTF recommendations; and the American College of Physicians (ACP) develops recommendations based on


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InternalMed_Harrison. (Table 100-3); the American Academy of Family Practitioners (AAFP) generally follow/ endorse the USPSTF recommendations; and the American College of Physicians (ACP) develops recommendations based on structured reviews of other organizations’ guidelines.


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InternalMed_Harrison. Breast cancer Breast self-examination, clinical breast examination by a caregiver, mammography, and magnetic resonance imaging (MRI) have all been variably advocated as useful screening tools.


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InternalMed_Harrison. A number of trials have suggested that annual or biennial screening with mammography or mammography plus clinical breast examination in normal-risk women older than age 50 years decreases breast cancer mortality. Each trial has been criticized for design flaws. In most trials, breast cancer mortality rate is decreased by 15–30%. Experts disagree on whether average-risk women age 40–49 years should receive regular screening (Table 100-3). The U.K. Age Trial, the only randomized trial of breast cancer screening to specifically evaluate the impact of mammography in women age 40–49 years, found no statistically significant difference in breast cancer mortality for screened women versus controls after about 11 years of follow-up (relative risk 0.83; 95% confidence interval 0.66–1.04); however, <70% of women received screening in the intervention arm, potentially diluting the observed effect. A meta-analysis of eight large randomized trials showed a 15% relative reduction in mortality


InternalMed_Harrison

InternalMed_Harrison. <70% of women received screening in the intervention arm, potentially diluting the observed effect. A meta-analysis of eight large randomized trials showed a 15% relative reduction in mortality (relative risk 0.85; 95% confidence interval 0.75–0.96) from mammography screening for women age 39–49 years after 11–20 years of follow-up. This is equivalent to a number needed to invite to screening of 1904 over 10 years to prevent one breast cancer death. At the same time, nearly half of women age 40–49 years screened annually will have false-positive mammograms necessitating further evaluation, often including biopsy. Estimates of overdiagnosis range from 10 to 40% of diagnosed invasive cancers. In the United States, widespread screening over the last several decades has not been accompanied by a reduction in incidence of metastatic breast cancer despite a large increase in early-stage disease, suggesting a substantial amount of overdiagnosis at the population level.


InternalMed_Harrison

InternalMed_Harrison. No study of breast self-examination has shown it to decrease mortality. A randomized controlled trial of approximately 266,000 women in China demonstrated no difference in breast cancer mortality between a group that received intensive breast self-exam instruction and reinforcement/reminders and controls at 10 years of follow-up. However, more benign breast lesions were discovered and more breast biopsies were performed in the self-examination arm.


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InternalMed_Harrison. Genetic screening for BRCA1 and BRCA2 mutations and other markers of breast cancer risk has identified a group of women at high risk for breast cancer. Unfortunately, when to begin and the optimal frequency of screening have not been defined. Mammography is less sensitive at detecting breast cancers in women carrying BRCA1 and BRCA2 mutations, possibly because such cancers occur in younger women, in whom mammography is known to be less sensitive. MRI screening may be more sensitive than mammography in women at high risk due to genetic predisposition or in women with very dense breast tissue, but specificity may be lower. An increase in overdiagnosis may accompany the higher sensitivity. The impact of MRI on breast cancer mortality with or without concomitant use of mammography has not been evaluated in a randomized controlled trial.


InternalMed_Harrison

InternalMed_Harrison. cervical cancer Screening with Papanicolaou (Pap) smears decreases cervical cancer mortality. The cervical cancer mortality rate has fallen substantially since the widespread use of the Pap smear. With the onset of sexual activity comes the risk of sexual transmission of HPV, the fundamental etiologic factor for cervical cancer. Screening guidelines recommend regular Pap testing for all women who have reached the age of 21 (prior to this age, even in individuals that have begun sexual activity, screening may cause more harm than benefit). The recommended interval for Pap screening is 3 years. Screening more frequently adds little benefit but leads to important harms, including unnecessary procedures and overtreatment of transient lesions. Beginning at age 30, guidelines also offer the alternative of combined Pap smear and HPV testing for women. The screening interval for women who test normal using this approach may be lengthened to 5 years.


InternalMed_Harrison

InternalMed_Harrison. An upper age limit at which screening ceases to be effective is not known, but women age 65 years with no abnormal results in the previous 10 years may choose to stop screening. Screening should be Women ≥40 years: “I” (as a standalone without mammography) Women 40–49 years: The decision should be an individual one, and take patient context/values into account (“C”) Women 50–74 years: Every 2 years (“B”) Women ≥75 years: “I” Women 21–65 years: Screen every 3 years (“A”) Women <21 years: “D” Women >65 years, with adequate, normal prior Pap screenings: “D” Women after total hysterectomy for noncancerous causes: “D” Women 30–65 years: Screen in combination with cytology every 5 years if woman desires to lengthen the screening interval (see Pap test, above) (“A”) Women <30 years: “D” Women >65 years, with adequate, normal prior Pap screenings: “D” Women after total hysterectomy for noncancerous causes: “D”


InternalMed_Harrison

InternalMed_Harrison. Women <30 years: “D” Women >65 years, with adequate, normal prior Pap screenings: “D” Women after total hysterectomy for noncancerous causes: “D” Adults 50–75 years: every 5 years in combination with high-sensitivity FOBT every 3 years (“A”)b Adults 76–85 years: “C” Adults ≥85 years: “D” Adults 50–75 years: Annually, for high-sensitivity FOBT (“A”) Adults 76–85 years: “C” Adults ≥85 years: “D” Adults 50–75 years: every 10 years (“A”) Adults 76–85 years: “C” Adults ≥85 years: “D” Adults 55–80 years, with a ≥30 pack-year smoking history, still smoking or have quit within past 15 years. Discontinue once a person has not smoked for 15 years or develops a health problem that substantially limits life expectancy or the ability to have curative lung surgery: “B” “D” Women ≥20 years: Breast self-exam is an option Women 20–39 years: Perform every 3 years Women ≥40 years: Perform annually Women ≥40 years: Screen annually for as long as the woman is in good health


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InternalMed_Harrison. Women with >20% lifetime risk of breast cancer: Screen with MRI plus mammography annually Women with 15–20% lifetime risk of breast cancer: Discuss option of MRI plus mammography annually Women with <15% lifetime risk of breast cancer: Do not screen annually with MRI Women 21–29 years: Screen every 3 years Women 30–65 years: Acceptable approach to screen with cytology every 3 years (see HPV test below) Women <21 years: No screening Women >65 years: No screening following adequate negative prior screening Women after total hysterectomy for noncancerous causes: Do not screen Women 30–65 years: Preferred approach to screen with HPV and cytology co-testing every 5 years (see Pap test above) Women <30 years: Do not use HPV testing Women >65 years: No screening following adequate negative prior screening Women after total hysterectomy for noncancerous causes: Do not screen Adults ≥50 years: Screen every 5 years Adults ≥50 years: Screen every year


InternalMed_Harrison

InternalMed_Harrison. Women after total hysterectomy for noncancerous causes: Do not screen Adults ≥50 years: Screen every 5 years Adults ≥50 years: Screen every year Adults ≥50 years: Screen every 10 years Adults ≥50 years: Screen, but interval uncertain Adults ≥50 years: Screen every year Adults ≥50 years: Screen every 5 years Men and women, 55–74 years, with ≥30 pack-year smoking history, still smoking or have quit within past 15 years: Discuss benefits, limitations, and potential harms of screening; only perform screening in facilities with the right type of CT scanner and with high expertise/specialists There is no sufficiently accurate test proven effective in the early detection of ovarian cancer. For women at high risk of ovarian cancer and/or who have unexplained, persistent symptoms, the combination of CA-125 and transvaginal ultrasound with pelvic exam may be offered. Prevention and Early Detection of Cancer Skin Complete skin examination by clinician or patient Men, all ages: “D”


InternalMed_Harrison

InternalMed_Harrison. Prevention and Early Detection of Cancer Skin Complete skin examination by clinician or patient Men, all ages: “D” Starting at age 50, men should talk to a doctor about the pros and cons of testing so they can decide if testing is the right choice for them. If African American or have a father or brother who had prostate cancer before age 65, men should have this talk starting at age 45. How often they are tested will depend on their PSA level. As for PSA; if men decide to be tested, they should have the PSA blood test with or without a rectal exam


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InternalMed_Harrison. Self-examination monthly; clinical exam as part of routine cancer-related checkup aSummary of the screening procedures recommended for the general population by the USPSTF and the ACS. These recommendations refer to asymptomatic persons who are not known to have risk factors, other than age or gender, for the targeted condition. bUSPSTF lettered recommendations are defined as follows: “A”: The USPSTF recommends the service, because there is high certainty that the net benefit is substantial; “B”: The USPSTF recommends the service, because there is high certainty that the net benefit is moderate or moderate certainty that the net benefit is moderate to substantial; “C”: The USPSTF recommends selectively offering or providing this service to individual patients based on professional judgment and patient preferences; there is at least moderate certainty that the net benefit is small; “D”: The USPSTF recommends against the service because there is moderate or high certainty that the


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InternalMed_Harrison. and patient preferences; there is at least moderate certainty that the net benefit is small; “D”: The USPSTF recommends against the service because there is moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits; “I”: The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of the service.


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InternalMed_Harrison. Abbreviations: ACS, American Cancer Society; USPSTF, U.S. Preventive Services Task Force. discontinued in women who have undergone a hysterectomy for noncancerous reasons. Although the efficacy of the Pap smear in reducing cervical cancer mortality has never been directly confirmed in a randomized, controlled setting, a clustered randomized trial in India evaluated the impact of one-time cervical visual inspection and immediate colposcopy, biopsy, and/or cryotherapy (where indicated) versus counseling on cervical cancer deaths in women age 30–59 years. After 7 years of follow-up, the age-standardized rate of death due to cervical cancer was 39.6 per 100,000 person-years in the intervention group versus 56.7 per 100,000 person-years in controls.


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InternalMed_Harrison. colorectal cancer Fecal occult blood testing (FOBT), digital rectal examination (DRE), rigid and flexible sigmoidoscopy, colonoscopy, and computed tomography (CT) colonography have been considered for colorectal cancer screening. A meta-analysis of four randomized controlled trials demonstrated a 15% relative reduction in colorectal cancer mortality with FOBT. The sensitivity for FOBT is increased if specimens are rehydrated before testing, but at the cost of lower specificity. The false-positive rate for rehydrated FOBT is high; 1–5% of persons tested have a positive test. Only 2–10% of those with occult blood in the stool have cancer. The high false-positive rate of FOBT dramatically increases the number of colonoscopies performed.


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InternalMed_Harrison. Fecal immunochemical tests appear to have higher sensitivity for colorectal cancer than nonrehydrated FOBT tests. Fecal DNA testing is an emerging testing modality; it may have increased sensitivity and comparable specificity to FOBT and could potentially reduce harms associated with follow-up of false-positive tests. The body of evidence on the operating characteristics and effectiveness of fecal DNA tests in reducing colorectal cancer mortality is limited.


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InternalMed_Harrison. Two meta-analyses of five randomized controlled trials of sigmoidoscopy (i.e., the NORCCAP, SCORE, PLCO, Telemark, and U.K. trials) found an 18% relative reduction in colorectal cancer incidence and a 28% relative reduction in colorectal cancer mortality. Participant ages ranged from 50 to 74 years, with follow-up ranging from 6 to 13 years. Diagnosis of adenomatous polyps by sigmoidoscopy should lead to evaluation of the entire colon with colonoscopy. The most efficient interval for screening sigmoidoscopy is unknown, but an interval of 5 years is often recommended. Case-control studies suggest that intervals of up to 15 years may confer benefit; the U.K. trial demonstrated benefit with one-time screening.


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InternalMed_Harrison. One-time colonoscopy detects ∼25% more advanced lesions (polyps >10 mm, villous adenomas, adenomatous polyps with high-grade dysplasia, invasive cancer) than one-time FOBT with sigmoidoscopy; comparative programmatic performance of the two modalities over time is not known. Perforation rates are about 3/1000 for colonoscopy and 1/1000 for sigmoidoscopy. Debate continues on whether colonoscopy is too expensive and invasive and whether sufficient provider capacity exists to be recommended as the preferred screening tool in standard-risk populations. Some observational studies suggest that efficacy of colonoscopy to decrease colorectal cancer mortality is primarily limited to the left side of the colon.


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InternalMed_Harrison. CT colonography, if done at expert centers, appears to have a sensitivity for polyps ≥6 mm comparable to colonoscopy. However, the rate of extracolonic findings of abnormalities of uncertain significance that must nevertheless be worked up is high (∼15–30%); the long-term cumulative radiation risk of repeated colonography screenings is also a concern.


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InternalMed_Harrison. lung cancer Chest x-ray and sputum cytology have been evaluated in several randomized lung cancer screening trials. The most recent and largest (n = 154,901) of these, one substudy of the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial, found that, compared with usual care, annual chest x-ray did not reduce the risk of dying from lung cancer (relative risk 0.99; 95% confidence interval 0.87–1.22) after 13 years. Low-dose CT has also been evaluated in several randomized trials. The largest and longest of these, the National Lung Screening Trial (NLST), was a randomized controlled trial of screening for lung cancer in approximately 53,000 persons age 55–74 years with a 30+ pack-year smoking history. It demonstrated a statistically significant relative reduction of about 15–20% in lung cancer mortality in the CT arm compared to the chest x-ray arm (or about 3 fewer deaths per 1000 people screened with CT). However, the harms include the potential radiation risks


InternalMed_Harrison

InternalMed_Harrison. 15–20% in lung cancer mortality in the CT arm compared to the chest x-ray arm (or about 3 fewer deaths per 1000 people screened with CT). However, the harms include the potential radiation risks associated with multiple scans, the discovery of incidental findings of unclear significance, and a high rate of false-positive test results. Both incidental findings and false-positive tests can lead to invasive diagnostic procedures associated with anxiety, expense, and complications (e.g., pneumoor hemothorax after lung biopsy). The NLST was performed at experienced screening centers, and the balance of benefits and harms may differ in the community setting at less experienced centers.


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InternalMed_Harrison. ovarian cancer Adnexal palpation, transvaginal ultrasound (TVUS), and serum CA-125 assay have been considered for ovarian cancer screening. A large randomized controlled trial has shown that an annual screening program of TVUS and CA-125 in average-risk women does not reduce deaths from ovarian cancer (relative risk 1.21; 95% confidence interval 0.99–1.48). Adnexal palpation was dropped early in the study because it did not detect any ovarian cancers that were not detected by either TVUS or CA-125. The risks and costs associated with the high number of false-positive results are impediments to routine use of these modalities for screening. In the PLCO trial, 10% of participants had a false-positive result from TVUS or CA-125, and one-third of these women underwent a major surgical procedure; the ratio of surgeries to screen-detected ovarian cancer was approximately 20:1.


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InternalMed_Harrison. Prostate cancer The most common prostate cancer screening modalities are DRE and serum PSA assay. An emphasis on PSA screening has caused prostate cancer to become the most common nonskin cancer diagnosed in American males. This disease is prone to lead-time bias, length bias, and overdiagnosis, and substantial debate continues among experts as to whether screening should be offered unless the patient specifically asks to be screened. Virtually all organizations stress the importance of informing men about the uncertainty regarding screening efficacy and the harms associated with screening. Prostate cancer screening clearly detects many asymptomatic cancers, but the ability to distinguish tumors that are lethal but still curable from those that pose little or no threat to health is limited, and randomized trials indicate that the effect of PSA screening on prostate cancer mortality across a population is, at best, small. Men older than age 50 years have a high prevalence of indolent,


InternalMed_Harrison

InternalMed_Harrison. and randomized trials indicate that the effect of PSA screening on prostate cancer mortality across a population is, at best, small. Men older than age 50 years have a high prevalence of indolent, clinically insignificant prostate cancers (about 30–50% of men, increasing further as men age).


InternalMed_Harrison

InternalMed_Harrison. Two major randomized controlled trials of the impact of PSA screening on prostate cancer mortality have been published. The PLCO Cancer Screening Trial was a multicenter U.S. trial that randomized almost 77,000 men age 55–74 years to receive either annual PSA testing for 6 years or usual care. At 13 years of follow-up, no statistically significant difference in the number of prostate cancer deaths were noted between the arms (rate ratio 1.09; 95% confidence interval 0.87–1.36). Approximately 50% of men in the control arm received at least one PSA test during the trial, which may have potentially diluted a small effect.


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InternalMed_Harrison. The European Randomized Study of Screening for Prostate Cancer (ERSPC) was a multinational study that randomized approximately 182,000 men between age 50 and 74 years (with a predefined “core” screening group of men age 55–69 years) to receive PSA testing or no screening. Recruitment and randomization procedures, as well as actual frequency of PSA testing, varied by country. After a median follow-up of 11 years, a 20% relative reduction in the risk of prostate cancer death in the screened arm was noted in the “core” screening group. The trial found that 1055 men would need to be invited to screening, and 37 cases of prostate cancer detected, to avert 1 death from prostate cancer. Of the seven countries included in the mortality analysis, two demonstrated statistically significant reductions in prostate cancer deaths, whereas five did not. There was also an imbalance in treatment between the two study arms, with a higher proportion of men with clinically localized cancer receiving


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InternalMed_Harrison. in prostate cancer deaths, whereas five did not. There was also an imbalance in treatment between the two study arms, with a higher proportion of men with clinically localized cancer receiving radical prostatectomy in the screening arm and receiving it at experienced referral centers.


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InternalMed_Harrison. Treatments for low-stage prostate cancer, such as surgery and radiation therapy, can cause significant morbidity, including impotence and urinary incontinence. In a trial conducted in the United States after the initiation of widespread PSA testing, random assignment to radical prostatectomy compared with “watchful waiting” did not result in a statistically significant decrease in prostate cancer deaths (absolute risk reduction 2.7%; 95% confidence interval–1.3 to 6.2%). skIn cancer Visual examination of all skin surfaces by the patient or by a health care provider is used in screening for basal and squamous cell cancers and melanoma. No prospective randomized study has been performed to look for a mortality decrease. Unfortunately, screening is associated with a substantial rate of overdiagnosis. Prevention and Early Detection of Cancer


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InternalMed_Harrison. Prevention and Early Detection of Cancer Cancer Genetics Pat J. Morin, Jeffrey M. Trent, Francis S. Collins, Bert Vogelstein CANCER IS A GENETIC DISEASE Cancer arises through a series of somatic alterations in DNA that 101e


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InternalMed_Harrison. APC inactivation or ˜-catenin activation Early adenoma Intermed adenoma Late adenoma Carcinoma Metastasis K-RAS or BRAFactivation SMAD4or TGF˜ II inactivation P53inactivation Other alterations Microsatellite Instability (MIN) or Chromosomal Instability (CIN) Normal epithelium FIGURE 101e-2 Progressive somatic mutational steps in the development of colon carcinoma. The accumulation of alterations in a num-ber of different genes results in the progression from normal epithelium through adenoma to full-blown carcinoma. Genetic instability (micro-satellite or chromosomal) accelerates the progression by increasing the likelihood of mutation at each step. Patients with familial polyposis are already one step into this pathway, because they inherit a germline alteration of the APC gene. TGF, transforming growth factor.


InternalMed_Harrison

InternalMed_Harrison. result in unrestrained cellular proliferation. Most of these alterations involve actual sequence changes in DNA (i.e., mutations). They may originate as a consequence of random replication errors, exposure to carcinogens (e.g., radiation), or faulty DNA repair processes. While most cancers arise sporadically, familial clustering of cancers occurs in certain families that carry a germline mutation in a cancer gene.


InternalMed_Harrison

InternalMed_Harrison. The idea that cancer progression is driven by sequential somatic mutations in specific genes has only gained general acceptance in the past 25 years. Before the advent of the microscope, cancer was believed to be composed of aggregates of mucus or other noncellular matter. By the middle of the nineteenth century, it became clear that tumors were masses of cells and that these cells arose from the normal cells of the tissue from which the cancer originated. However, the molecular basis for the uncontrolled proliferation of cancer cells was to remain a mystery for another century. During that time, a number of theories for the origin of cancer were postulated. The great biochemist Otto Warburg proposed the combustion theory of cancer, which stipulated that cancer was due to abnormal oxygen metabolism. In addition, some believed that all cancers were caused by viruses, and that cancer was in fact a contagious disease.


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InternalMed_Harrison. In the end, observations of cancer occurring in chimney sweeps, studies of x-rays, and the overwhelming data demonstrating cigarette smoke as a causative agent in lung cancer, together with Ames’s work on chemical mutagenesis, provided convincing evidence that cancer originated through changes in DNA. Although the viral theory of cancer did not prove to be generally accurate (with the exception of human papillomaviruses, which can cause cervical and other cancers in human), the study of retroviruses led to the discovery of the first human oncogenes in the late 1970s. Soon after, the study of families with genetic predisposition to cancer was instrumental in the discovery of tumor-suppressor genes. The field that studies the type of mutations, as well as the consequence of these mutations in tumor cells, is now known as cancer genetics. Nearly all cancers originate from a single cell; this clonal origin is a critical discriminating feature between neoplasia and hyperplasia.


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InternalMed_Harrison. Nearly all cancers originate from a single cell; this clonal origin is a critical discriminating feature between neoplasia and hyperplasia. FIGURE 101e-1 Multistep clonal development of malignancy. In this diagram a series of five cumulative mutations (T , T , T , T , T ), each with a modest growth advantage acting alone, eventually results in a malignant tumor. Note that not all such alterations result in progression; for example, the T3 clone is a dead end. The actual number of cumulative mutations necessary to transform from the normal to the malignant state is unknown in most tumors. (After P Nowell: Science 194:23, 1976, with permission.)


InternalMed_Harrison

InternalMed_Harrison. Multiple cumulative mutational events are invariably required for the progression of a tumor from normal to fully malignant phenotype. The process can be seen as Darwinian microevolution in which, at each successive step, the mutated cells gain a growth advantage resulting in an increased representation relative to their neighbors (Fig. 101e-1). Based on observations of cancer frequency increases during aging, as well as molecular genetics work, it is believed that 5 to 10 accumulated mutations are necessary for a cell to progress from the normal to the fully malignant phenotype.


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InternalMed_Harrison. We are beginning to understand the precise nature of the genetic alterations responsible for some malignancies and to get a sense of the order in which they occur. The best-studied example is colon cancer, in which analyses of DNA from tissues extending from normal colon epithelium through adenoma to carcinoma have identified some of the genes mutated in the process (Fig. 101e-2). Other malignancies are believed to progress in a similar stepwise fashion, although the order and identity of genes affected may be different. TWO TYPES OF CANCER GENES: ONCOGENES AND TUMORSUPPRESSOR GENES There are two major types of cancer genes. The first type comprises genes that positively influence tumor formation and are known as oncogenes. The second type of cancer genes negatively impact tumor growth and have been named tumor-suppressor genes. Both oncogenes and tumor-suppressor genes exert their effects on tumor growth Abbreviations: AML, acute myeloid leukemia; CML, chronic myeloid leukemia.


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InternalMed_Harrison. through their ability to control cell division (cell birth) or cell death (apoptosis), although the mechanisms can be extremely complex. While tightly regulated in normal cells, oncogenes acquire mutations in cancer cells, and the mutations typically relieve this control and lead to increased activity of the gene products. This mutational event typically occurs in a single allele of the oncogene and acts in a dominant fashion. In contrast, the normal function of tumor-suppressor genes is usually to restrain cell growth, and this function is lost in cancer. Because of the diploid nature of mammalian cells, both alleles must be inactivated for a cell to completely lose the function of a tumor-suppressor gene, leading to a recessive mechanism at the cellular level. From these ideas and studies on the inherited form of retinoblastoma, Knudson and others formulated the two-hit hypothesis, which in its modern version states that both copies of a tumor-suppressor gene must be inactivated in


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InternalMed_Harrison. on the inherited form of retinoblastoma, Knudson and others formulated the two-hit hypothesis, which in its modern version states that both copies of a tumor-suppressor gene must be inactivated in cancer.


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InternalMed_Harrison. There is a subset of tumor-suppressor genes, the caretaker genes, that do not affect cell growth directly, but rather control the ability of the cell to maintain the integrity of its genome. Cells with a deficiency in these genes have an increased rate of mutations throughout their genomes, including in oncogenes and tumor-suppressor genes. This “mutator” phenotype was first hypothesized by Loeb to explain how the multiple mutational events required for tumorigenesis can occur in the lifetime of an individual. A mutator phenotype has now been observed in some forms of cancer, such as those associated with deficiencies in DNA mismatch repair. The great majority of cancers, however, do not harbor repair deficiencies, and their rate of mutation is similar to that observed in normal cells. Many of these cancers, however, appear to harbor a different kind of genetic instability, affecting the loss or gains of whole chromosomes or large parts thereof (as explained in more detail below).


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InternalMed_Harrison. Work by Peyton Rous in the early 1900s revealed that a chicken sarcoma could be transmitted from animal to animal in cell-free extracts, suggesting that cancer could be induced by an agent acting positively to promote tumor formation. The agent responsible for the transmission of the cancer was a retrovirus (Rous sarcoma virus, RSV) and the oncogene responsible was identified 75 years later as v-src. Other oncogenes were also discovered through their presence in the genomes of retroviruses that are capable of causing cancers in chickens, mice, and rats. The cellular homologues of these viral genes are called protooncogenes and are often targets of mutation or aberrant regulation in human cancer. Whereas many oncogenes were discovered because of their presence in retroviruses, other oncogenes, particularly those involved in translocations characteristic of particular leukemias and lymphomas, were isolated through genomic approaches. Investigators cloned the sequences surrounding the


InternalMed_Harrison

InternalMed_Harrison. particularly those involved in translocations characteristic of particular leukemias and lymphomas, were isolated through genomic approaches. Investigators cloned the sequences surrounding the chromosomal translocations observed cytogenetically and then deduced the nature of the genes that were the targets of these translocations (see below). Some of these were oncogenes known from retroviruses (like ABL, involved in chronic myeloid leukemia [CML]), whereas others were new (like BCL2, involved in B cell lymphoma). In the normal cellular environment, protooncogenes have crucial roles in cell proliferation and differentiation. Table 101e-1 is a partial list of oncogenes known to be involved in human cancer.


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InternalMed_Harrison. The normal growth and differentiation of cells is controlled by growth factors that bind to receptors on the surface of the cell. The signals generated by the membrane receptors are transmitted inside the cells through signaling cascades involving kinases, G proteins, and other regulatory proteins. Ultimately, these signals affect the activity of transcription factors in the nucleus, which regulate the expression of genes crucial in cell proliferation, cell differentiation, and cell death. Oncogene products have been found to function at critical steps in these pathways (Chap. 102e), and inappropriate activation of these pathways can lead to tumorigenesis.


InternalMed_Harrison

InternalMed_Harrison. Point mutation is a common mechanism of oncogene activation. For example, mutations in one of the RAS genes (HRAS, KRAS, or NRAS) are present in up to 85% of pancreatic cancers and 45% of colon cancers but are less common in other cancer types, although they can occur at significant frequencies in leukemia, lung, and thyroid cancers. Remarkably—and in contrast to the diversity of mutations found in tumor-suppressor genes (see below)—most of the activated RAS genes contain point mutations in codons 12, 13, or 61 (these mutations reduce RAS GTPase activity, leading to constitutive activation of the mutant RAS protein). The restricted pattern of mutations observed in oncogenes compared to that of tumor-suppressor genes reflects the fact that gain-of-function mutations are less likely to occur than mutations that simply lead to loss of activity. Indeed, inactivation of a gene can in theory be accomplished through the introduction of a stop codon anywhere in the coding sequence, whereas


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InternalMed_Harrison. than mutations that simply lead to loss of activity. Indeed, inactivation of a gene can in theory be accomplished through the introduction of a stop codon anywhere in the coding sequence, whereas activations require precise substitutions at residues that can somehow lead to an increase in the activity of the encoded protein. Importantly, the specificity of oncogene mutations provides diagnostic opportunities, as tests that identify mutations at defined positions are easier to design than tests aimed at detecting random changes in a gene.


InternalMed_Harrison

InternalMed_Harrison. The second mechanism for activation of oncogenes is DNA sequence amplification, leading to overexpression of the gene product. This increase in DNA copy number may cause cytologically recognizable chromosome alterations referred to as homogeneous staining regions (HSRs) if integrated within chromosomes, or double minutes (dmins) if extrachromosomal. The recognition of DNA amplification is accomplished through various cytogenetic techniques such as comparative genomic hybridization (CGH) or fluorescence in situ hybridization (FISH), which allow the visualization of chromosomal aberrations using fluorescent dyes. In addition, noncytogenetic, microarray-based approaches are now available for identifying changes in copy number at high resolution. Newer short-tag–based sequencing approaches have been used to evaluate amplifications. When paired with next-generation sequencing, this approach offers the highest degree of resolution and quantification available. With both microarray and


InternalMed_Harrison

InternalMed_Harrison. have been used to evaluate amplifications. When paired with next-generation sequencing, this approach offers the highest degree of resolution and quantification available. With both microarray and sequencing technologies, the entire genome can be surveyed for gains and losses of DNA sequences, thus pinpointing chromosomal regions likely to contain genes important in the development or progression of cancer.


InternalMed_Harrison

InternalMed_Harrison. Numerous genes have been reported to be amplified in cancer. Several of these genes, including NMYC and LMYC, were identified through their presence within the amplified DNA sequences of a tumor and had homology to known oncogenes. Because the region amplified often includes hundreds of thousands of base pairs, multiple oncogenes may be amplified in a single amplicon in some cancers (particularly in sarcomas). Indeed, MDM2, GLI, CDK4, and SAS at chromosomal location 12q13-15 have been shown to be simultaneously amplified in several types of sarcomas and other tumors. Amplification of a cellular gene is often a predictor of poor prognosis; for example, ERBB2/HER2 and NMYC are often amplified in aggressive breast cancers and neuroblastoma, respectively.


InternalMed_Harrison

InternalMed_Harrison. Chromosomal alterations provide important clues to the genetic changes in cancer. The chromosomal alterations in human solid tumors such as carcinomas are heterogeneous and complex and occur as a result of the frequent chromosomal instability (CIN) observed in these tumors (see below). In contrast, the chromosome alterations in myeloid and lymphoid tumors are often simple translocations, i.e., reciprocal transfers of chromosome arms from one chromosome to another. Consequently, many detailed and informative chromosome analyses have been performed on hematopoietic cancers. The breakpoints of recurring chromosome abnormalities usually occur at the site of cellular oncogenes. Table 101e-2 lists representative examples of recurring chromosome alterations in malignancy and the associated gene(s) rearranged or deregulated by the chromosomal rearrangement. Translocations are particularly common in lymphoid tumors, probably because these cell types have the capability to rearrange their DNA


InternalMed_Harrison

InternalMed_Harrison. rearranged or deregulated by the chromosomal rearrangement. Translocations are particularly common in lymphoid tumors, probably because these cell types have the capability to rearrange their DNA to generate antigen receptors. Indeed, antigen receptor genes are commonly involved in the translocations, implying that an imperfect regulation of receptor gene rearrangement may be involved in the pathogenesis. An interesting example is Burkitt’s lymphoma, a B cell tumor characterized by a reciprocal translocation between chromosomes 8 and 14. Molecular analysis of Burkitt’s lymphomas demonstrated that the breakpoints occurred within or near the MYC locus on chromosome 8 and within the immunoglobulin heavy chain locus on chromosome 14, resulting in the transcriptional activation of MYC. Enhancer activation by translocation, although not universal, appears to play an important role in malignant progression. In addition to transcription factors and signal transduction molecules, translocation


InternalMed_Harrison

InternalMed_Harrison. activation by translocation, although not universal, appears to play an important role in malignant progression. In addition to transcription factors and signal transduction molecules, translocation may result in the overexpression of cell cycle


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InternalMed_Harrison. Source: From R Hesketh: The Oncogene and Tumour Suppressor Gene Facts Book, 2nd ed. San Diego, Academic Press, 1997; with permission. regulatory proteins or proteins such as cyclins and of proteins that regulate cell death.


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InternalMed_Harrison. The first reproducible chromosome abnormality detected in human malignancy was the Philadelphia chromosome detected in CML. This cytogenetic abnormality is generated by reciprocal translocation involving the ABL oncogene on chromosome 9, encoding a tyrosine kinase, being placed in proximity to the BCR (breakpoint cluster region) gene on chromosome 22. Figure 101e-3 illustrates the generation of the translocation and its protein product. The consequence of expression of the BCR-ABL gene product is the activation of signal transduction pathways leading to cell growth independent of normal external signals. Imatinib (marketed as Gleevec), a drug that specifically blocks the activity of Abl tyrosine kinase, has shown remarkable efficacy with little toxicity in patients with CML. It is hoped that knowledge of genetic alterations in other cancers will likewise lead to mechanism-based design and development of a new generation of chemotherapeutic agents.


InternalMed_Harrison

InternalMed_Harrison. Solid tumors are generally highly aneuploid, containing an abnormal number of chromosomes; these chromosomes also exhibit structural alterations such as translocations, deletions, and amplifications. These abnormalities are collectively referred to as chromosomal instability (CIN). Normal cells possess several cell cycle checkpoints, essentially quality-control requirements that have to be met before subsequent events are allowed to take place. The mitotic checkpoint, which ensures proper chromosome attachment to the mitotic spindle before allowing the sister chromatids to separate, is altered in certain cancers. The molecular basis of CIN remains unclear, although a number of mitotic checkpoint genes are found mutated or abnormally expressed in various tumors. The exact effects of these changes on the mitotic checkpoint are unknown, and both weakening and overactivation of the checkpoint have been proposed. The identification of the cause of CIN


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InternalMed_Harrison. FIGURE 101e-3 Specific translocation seen in chronic myeloid leukemia (CML). The Philadelphia chromosome (Ph) is derived from a reciprocal translocation between chromosomes 9 and 22 with the breakpoint joining the sequences of the ABL oncogene with the BCR gene. The fusion of these DNA sequences allows the generation of an entirely novel fusion protein with modified function. in tumors will likely be a formidable task, considering that several hundred genes are thought to control the mitotic checkpoint and other cellular processes ensuring proper chromosome segregation. Regardless of the mechanisms underlying CIN, the measurement of the number of chromosomal alterations present in tumors is now possible with both cytogenetic and molecular techniques, and several studies have shown that this information can be useful for prognostic purposes. In addition, because the mitotic checkpoint is essential for cellular viability, it may become a target for novel therapeutic approaches.


InternalMed_Harrison

InternalMed_Harrison. The first indication of the existence of tumor-suppressor genes came from experiments showing that fusion of mouse cancer cells with normal mouse fibroblasts led to a nonmalignant phenotype in the fused cells. The normal role of tumor-suppressor genes is to restrain cell growth, and the function of these genes is inactivated in cancer. The two major types of somatic lesions observed in tumor-suppressor genes during tumor development are point mutations and large deletions. Point mutations in the coding region of tumor-suppressor genes will frequently lead to truncated protein products or otherwise nonfunctional proteins. Similarly, deletions lead to the loss of a functional product and sometimes encompass the entire gene or even the entire chromosome arm, leading to loss of heterozygosity (LOH) in the tumor DNA compared to the corresponding normal tissue DNA (Fig. 101e-4). LOH in tumor DNA is considered a hallmark for the presence of a tumor-suppressor gene at a particular chromosomal


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InternalMed_Harrison. (LOH) in the tumor DNA compared to the corresponding normal tissue DNA (Fig. 101e-4). LOH in tumor DNA is considered a hallmark for the presence of a tumor-suppressor gene at a particular chromosomal location, and LOH studies have been useful in the positional cloning of many tumor-suppressor genes.


InternalMed_Harrison

InternalMed_Harrison. Gene silencing, an epigenetic change that leads to the loss of gene expression and occurs in conjunction with hypermethylation of the promoter and histone deacetylation, is another mechanism of tumor-suppressor gene inactivation. (An epigenetic modification refers to a change in the genome, heritable by cell progeny, that does not involve a change in the DNA sequence. The inactivation of the second X chromosome in female cells is an example of an epigenetic silencing that prevents gene expression from the inactivated chromosome.) During embryologic development, regions of chromosomes from one parent are silenced and gene expression proceeds from the chromosome of the other parent. For most genes, expression occurs from both alleles or randomly from one allele or the other. The preferential expression of a particular gene exclusively from the allele contributed by one parent is called parental imprinting and is thought to be regulated by covalent modifications of chromatin protein and


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InternalMed_Harrison. expression of a particular gene exclusively from the allele contributed by one parent is called parental imprinting and is thought to be regulated by covalent modifications of chromatin protein and DNA (often methylation) of the silenced allele.


InternalMed_Harrison

InternalMed_Harrison. The role of epigenetic control mechanisms in the development of human cancer is unclear. However, a general decrease in the level of DNA methylation has been noted as a common change in cancer. In addition, numerous genes, including some tumor-suppressor genes, appear to become hypermethylated and silenced during tumorigenesis. VHL and p16INK4 are well-studied examples of such tumor-suppressor genes. Overall, epigenetic mechanisms may be responsible for reprogramming the expression of a large number of genes in cancer and, together with the mutation of specific genes, are likely to be crucial in the development of human malignancies. The use of drugs that can reverse epigenetic changes in cancer cells may represent a novel therapeutic option in certain cancers or premalignant conditions. For example, demethylating agents (azacitidine or decitabine) are now approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients with high-risk myelodysplastic syndrome


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InternalMed_Harrison. For example, demethylating agents (azacitidine or decitabine) are now approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients with high-risk myelodysplastic syndrome (MDS).


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InternalMed_Harrison. A small fraction of cancers occur in patients with a genetic predisposition. In these families, the affected individuals have a predisposing loss-of-function mutation in one allele of a tumor-suppressor gene. The tumors in these patients show a loss of the remaining normal allele as a result of somatic events (point mutations or deletions), in agreement with the two-hit hypothesis (Fig. 101e-4). Thus, most cells of an individual with an inherited loss-of-function mutation in a tumor-suppressor gene are functionally normal, and only the rare cells that develop a mutation in the remaining normal allele will exhibit uncontrolled regulation.


InternalMed_Harrison

InternalMed_Harrison. Roughly 100 syndromes of familial cancer have been reported, although many are rare. The majority are inherited as autosomal dominant traits, although some of those associated with DNA repair abnormalities (xeroderma pigmentosum, Fanconi’s anemia, ataxia telangiectasia) are autosomal recessive. Table 101e-3 shows a number of cancer predisposition syndromes and the responsible genes. The current paradigm states that the genes mutated in familial syndromes can also be targets for somatic mutations in sporadic (noninherited) tumors. The study of cancer syndromes has thus provided invaluable insights into the mechanisms of progression for many tumor types. This section examines the case of inherited colon cancer in detail, but A1 Loss of normal chr 13 A3 B1 B3 Markers:


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InternalMed_Harrison. FIGURE 101e-4 Diagram of possible mechanisms for tumor formation in an individual with hereditary (familial) retinoblastoma. On the left is shown the pedigree of an affected individual who has inherited the abnormal (Rb) allele from her affected mother. The normal allele is shown as a (+). The four chromosomes of her two parents are drawn to indicate their origin. Flanking the retinoblastoma locus are microsatellite markers (A and B) also analyzed in this family. Markers A3 and B3 are on the chromosome carrying the retinoblastoma disease gene. Tumor formation results when the normal allele, which this patient inherited from her father, is inactivated. On the right are shown four possible ways in which this could occur. In each case, the resulting chromosome 13 arrangement is shown, as well as the results of PCR typing using the microsatellite markers comparing normal tissue (N) with tumor tissue (T). Note that in the first three situations, the normal allele (B1) has been lost in the


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InternalMed_Harrison. as the results of PCR typing using the microsatellite markers comparing normal tissue (N) with tumor tissue (T). Note that in the first three situations, the normal allele (B1) has been lost in the tumor tissue, which is referred to as loss of heterozygosity (LOH) at this locus.


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InternalMed_Harrison. similar lessons can be applied to many of the cancer syndromes listed in Table 101e-3. In particular, the study of inherited colon cancer will clearly illustrate the difference between two types of tumor-suppressor genes: the gatekeepers, which directly regulate the growth of tumors, and the caretakers, which, when mutated, lead to genetic instability and therefore act indirectly on tumor growth.


InternalMed_Harrison

InternalMed_Harrison. Familial adenomatous polyposis (FAP) is a dominantly inherited colon cancer syndrome due to germline mutations in the adenomatous polyposis coli (APC) tumor-suppressor gene on chromosome 5. Patients with this syndrome develop hundreds to thousands of adenomas in the colon. Each of these adenomas has lost the normal remaining allele of APC but has not yet accumulated the required additional mutations to generate fully malignant cells (Fig. 101e-2). The loss of the second functional APC allele in tumors from FAP families often occurs through loss of heterozygosity. However, out of these thousands of benign adenomas, several will invariably acquire further abnormalities and a subset will even develop into fully malignant cancers. APC is thus considered to be a gatekeeper for colon tumorigenesis: in the absence of mutation of this gatekeeper (or a gene acting within the same pathway), a colorectal tumor simply cannot form. Figure 101e-5 shows germline and somatic mutations found in the


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InternalMed_Harrison. in the absence of mutation of this gatekeeper (or a gene acting within the same pathway), a colorectal tumor simply cannot form. Figure 101e-5 shows germline and somatic mutations found in the APC gene. The function of the APC protein is still not completely understood, but it likely provides differentiation and apoptotic cues to colonic cells as they migrate up the crypts. Defects in this process may lead to abnormal accumulation of cells that should normally undergo apoptosis.


InternalMed_Harrison

InternalMed_Harrison. In contrast to patients with FAP, patients with hereditary nonpolyposis colon cancer (HNPCC, or Lynch’s syndrome) do not develop multiple polyposis, but instead develop only one or a small number of adenomas that rapidly progress to cancer. Most HNPCC cases are due to mutations in one of four DNA mismatch repair genes (Table 101e-3), which are components of a repair system that is normally responsible for correcting errors in freshly replicated DNA. Germline mutations in MSH2 and MLH1 account for more than 90% of HNPCC cases, whereas mutations in MSH6 and PMS2 are much less frequent. When a somatic mutation inactivates the remaining wild-type allele of a mismatch repair gene, the cell develops a hypermutable phenotype characterized by profound genomic instability, especially for the short repeated sequences called microsatellites. This microsatellite instability (MSI) favors the development of cancer by increasing the rate of mutations in many genes, including oncogenes and


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InternalMed_Harrison. the short repeated sequences called microsatellites. This microsatellite instability (MSI) favors the development of cancer by increasing the rate of mutations in many genes, including oncogenes and tumor-suppressor genes (Fig. 101e-2). These genes can thus be considered caretakers. Interestingly, CIN can also be found in colon cancer, but MSI and CIN appear to be mutually exclusive, suggesting that they represent alternative mechanisms for the generation of a mutator phenotype in this cancer (Fig. 101e-2). Other cancer types rarely exhibit MSI, but most exhibit CIN.


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InternalMed_Harrison. Although most autosomal dominant inherited cancer syndromes are due to mutations in tumor-suppressor genes (Table 101e-3), there are a few interesting exceptions. Multiple endocrine neoplasia type 2, a dominant disorder characterized by pituitary adenomas, medullary carcinoma of the thyroid, and (in some pedigrees) pheochromocytoma, is due to gain-of-function mutations in the protooncogene RET on chromosome 10. Similarly, gain-of-function mutations in the tyrosine kinase domain of the MET oncogene lead to hereditary papillary renal carcinoma. Interestingly, loss-of-function mutations in the RET gene cause a completely different disease, Hirschsprung’s disease (aganglionic megacolon [Chaps. 353 and 408]). Tuberous sclerosis TSC1 9q34 AD Angiofibroma, renal angiomyolipoma TSC2 16p13.3 von Hippel–Lindau VHL 3p25-26 AD Kidney, cerebellum, pheochromocytoma Abbreviations: AD, autosomal dominant; AR, autosomal recessive


InternalMed_Harrison

InternalMed_Harrison. Although the Mendelian forms of cancer have taught us much addition, the decision to test should depend on whether effective inter-about the mechanisms of growth control, most forms of cancer do not ventions exist for the particular type of cancer to be tested. Despite follow simple patterns of inheritance. In many instances (e.g., lung these caveats, genetic cancer testing for some cancer syndromes cancer), a strong environmental contribution is at work. Even in such already appears to have greater benefits than risks. Companies offer circumstances, however, some individuals may be more genetically genetic testing for many of the cancer syndromes listed in Table 83-3, susceptible to developing cancer, given the appropriate exposure, due including FAP (APC gene), hereditary breast and ovarian cancer to the presence of modifier alleles. syndrome (BRCA1 and BRCA2 genes), Lynch’s syndrome (mismatch repair genes), Li-Fraumeni syndrome (TP53 gene), Cowden syndrome (PTEN gene), hereditary


InternalMed_Harrison

InternalMed_Harrison. cancer to the presence of modifier alleles. syndrome (BRCA1 and BRCA2 genes), Lynch’s syndrome (mismatch repair genes), Li-Fraumeni syndrome (TP53 gene), Cowden syndrome (PTEN gene), hereditary retinoblastoma (RB1 gene), and others.


InternalMed_Harrison

InternalMed_Harrison. Because of the inherent problems of genetic testing such as cost, The discovery of cancer susceptibility genes raises the possibility of specificity, and sensitivity, it is not yet appropriate to offer these tests to DNA testing to predict the risk of cancer in individuals of affected fam-the general population. However, testing may be appropriate in some ilies. An algorithm for cancer risk assessment and decision making in subpopulations with a known increased risk, even without a defined high-risk families using genetic testing is shown in Fig. 101e-6. Once family history. For example, two mutations in the breast cancer susa mutation is discovered in a family, subsequent testing of asymptom-ceptibility gene BRCA1, 185delAG and 5382insC, exhibit a sufficiently atic family members can be crucial in patient management. A nega-high frequency in the Ashkenazi Jewish population that genetic testing tive gene test in these individuals can prevent years of anxiety in the of an individual of


InternalMed_Harrison

InternalMed_Harrison. in patient management. A nega-high frequency in the Ashkenazi Jewish population that genetic testing tive gene test in these individuals can prevent years of anxiety in the of an individual of this ethnic group may be warranted. knowledge that their cancer risk is no higher than that of the general As noted above, it is important that genetic test results be com-population. On the other hand, a positive test may lead to alteration of municated to families by trained genetic counselors, especially for clinical management, such as increased frequency of cancer screening high-risk high-penetrance conditions such as the hereditary breast and and, when feasible and appropriate, prophylactic surgery. Potential ovarian cancer syndrome (BRCA1/BRCA2). To ensure that the families negative consequences of a positive test result include psychologi-clearly understand its advantages and disadvantages and the impact it cal distress (anxiety, depression) and discrimination, although the may have on


InternalMed_Harrison

InternalMed_Harrison. of a positive test result include psychologi-clearly understand its advantages and disadvantages and the impact it cal distress (anxiety, depression) and discrimination, although the may have on disease management and psyche, genetic testing should Genetic Information Nondiscrimination Act (GINA) makes it illegal never be done before counseling. Significant expertise is needed to for predictive genetic information to be used to discriminate in health communicate the results of genetic testing to families. For example, insurance or employment. Testing should therefore not be conducted one common mistake is to misinterpret the result of negative genetic without counseling before and after disclosure of the test result. In tests. For many cancer predisposition genes, the sensitivity of genetic


InternalMed_Harrison

InternalMed_Harrison. Number of mutations oncogene, leading to its downregula-101e-7 tion in leukemic cells and apoptosis. As another example of miRNAs’ involvement in oncogenic pathways, the p53 tumor suppressor can transcriptionally induce miR-34 following genotoxic stress, and this induction is important in mediating p53 function. The expression of miRNAs is extremely specific, and there is evi- Number of mutations lineage and differentiation state, as well as cancer diagnosis and outcome prediction. Certain human malignancies are asso ciated with viruses. Examples include Burkitt’s lymphoma (Epstein-Barr virus; Chap. 218), hepatocellular car-Amino acid number cinoma (hepatitis viruses), cervical


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InternalMed_Harrison. FIGURE 101e-5 Germline and somatic mutations in the tumor-suppressor gene APC. APC cancer (human papillomavirus [HPV]; encodes a 2843-amino-acid protein with six major domains: an oligomerization region (O), armadillo Chap. 222), and T cell leukemia (retrepeats (ARM), 15-amino-acid repeats (15 aa), 20-amino-acid repeats (20 aa), a basic region, and a roviruses; Chap. 225e). The mechadomain involved in binding EB1 and the Drosophila discs large homologue (E/D). Shown are the nisms of action of these viruses are positions within the APC gene of a total of 650 somatic and 826 germline mutations (from the APC varied but always involve activation of database at http://www.umd.be/APC). The vast majority of these mutations result in the truncation of growth-promoting pathways or inhithe APC protein. Germline mutations are found to be relatively evenly distributed up to codon 1600 bition of tumor-suppressor products except for two mutation hotspots at amino acids 1061 and 1309, which together


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InternalMed_Harrison. Germline mutations are found to be relatively evenly distributed up to codon 1600 bition of tumor-suppressor products except for two mutation hotspots at amino acids 1061 and 1309, which together account for one-in the infected cells. For example, third of the mutations found in familial adenomatous polyposis (FAP) families. Somatic APC mutations HPV proteins E6 and E7 bind and in colon tumors cluster in an area of the gene known as the mutation cluster region (MCR). The loca-inactivate cellular tumor suppressors tion of the MCR suggests that the 20-amino-acid domain plays a crucial role in tumor suppression. p53 and pRB, respectively. There are testing is less than 70% (i.e., of 100 kindreds tested, disease-causing mutations can be identified in 70 at most). Therefore, such testing should in general begin with an affected member of the kindred (the youngest family member still alive who has had the cancer of interest). If a mutation is not identified in this individual, then the test


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InternalMed_Harrison. in general begin with an affected member of the kindred (the youngest family member still alive who has had the cancer of interest). If a mutation is not identified in this individual, then the test should be reported as noninformative (Fig. 101e-6) rather than negative (because it is possible that, for technical reasons, the mutation in this individual is not detectable by standard genetic assays). On the other hand, if a mutation can be identified in this individual, then testing of other family members can be performed, and the sensitivity of such subsequent tests will be 100% (because the mutation in the family is in this case known to be detectable by the method used).


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InternalMed_Harrison. MicroRNAs (miRNAs) are small noncoding RNAs 20–22 nucleotides in length that are involved in posttranscriptional gene regulation. Studies in chronic lymphocytic leukemia first suggested a link between miRNAs and cancer when miR-15 and miR-16 were found to be deleted or downregulated in the vast majority of tumors. Various miRNAs have since been found abnormally expressed in several human malignancies. Aberrant expression of miRNAs in cancer has been attributed to several mechanisms, such as chromosomal rearrangements, genomic copy number change, epigenetic modifications, defects in miRNA biogenesis pathway, and regulation by transcriptional factors. Somatic mutations of miRNAs have been identified in many cancers, but the exact functional consequences of these changes on cancer development remain to be determined. The SomaMir database (http://compbio.uthsc.edu/SomamiR) catalogs somatic and germ-line miRNA mutations that have been identified in cancer.


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InternalMed_Harrison. Functionally, miRNAs have been suggested to contribute to tumorigenesis through their ability to regulate oncogenic signaling pathways. For example, miR-15 and miR-16 have been shown to target the BCL2 several HPV types, and some of these types have been associated with the development of several malignancies, including cervical, vulvar, vaginal, penile, anal, and oropharyngeal cancer. Viruses are not sufficient for cancer development, but constitute one alteration in the multistep process of cancer progression.


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InternalMed_Harrison. The tumorigenesis process, driven by alterations in tumor suppressors, oncogenes, and epigenetic regulation, is accompanied by changes in gene expression. The advent of powerful techniques for high-throughput gene expression profiling, based on sequencing or microarrays, has allowed the comprehensive study of gene expression in neoplastic cells. It is indeed possible to identify the expression levels of thousands of genes expressed in normal and cancer tissues. Figure 101e-7 shows a typical microarray experiment examining gene expression in cancer. This global knowledge of gene expression allows the identification of differentially expressed genes and, in principle, the understanding of the complex molecular circuitry regulating normal and neoplastic behaviors. Such studies have led to molecular profiling of tumors, which has suggested general methods for distinguishing tumors of various biologic behaviors (molecular classification), elucidating pathways relevant to the development of


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InternalMed_Harrison. profiling of tumors, which has suggested general methods for distinguishing tumors of various biologic behaviors (molecular classification), elucidating pathways relevant to the development of tumors, and identifying molecular targets for the detection and therapy of cancer. The first practical applications of this technology have suggested that global gene expression profiling can provide prognostic information not evident from other clinical or laboratory tests. The Gene Expression Omnibus (GEO, http://www.ncbi.nlm.nih.gov/geo/) is a searchable online repository for expression profiling data.


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InternalMed_Harrison. With the completion of the Human Genome Project and advances in sequencing technologies, systematic mutational analysis of the cancer genome has become possible. In fact, whole genome sequencing of cancer cells is now possible, and this technology has the potential to Patients (1) from family with a known cancer syndrome, (2) from a family with a history of cancer, (3) with early onset cancer


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InternalMed_Harrison. Patients (1) from family with a known cancer syndrome, (2) from a family with a history of cancer, (3) with early onset cancer End of testing, noninformative Informed consent Testing of cancer patient Identification of disease-causing mutation Screening of asymptomatic family members Failure to identify mutations Review of family history to confirm/identify possible cancer syndromes and candidate genes Pretest counseling Positive test: family member requires increased screening or other interventions Negative test: family member has no increased risk of cancer FIGURE 101e-6 Algorithm for genetic testing in a family with can-cer predisposition. The key step is the identification of a mutation in a cancer patient, which allows testing of asymptomatic family mem-bers. Asymptomatic family members who test positive may require increased screening or surgery, whereas others are at no greater risk for cancer than the general population.


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InternalMed_Harrison. revolutionize our approach to cancer prevention, diagnosis, and treatment. The International Cancer Genome Consortium (http://icgc. org/) was developed by leading cancer agencies worldwide, genome and cancer scientists, and statisticians with the goal to launch and coordinate cancer genomics research projects worldwide and to disseminate the data. Hundreds of cancer genomes from at least 25 cancer types have been sequenced through various collaborative efforts. In addition, exome sequencing (sequencing all the coding regions of the genome) has also been performed on a large number of tumors. These sequencing data have been used to elucidate the mutational profile of cancer, including the identification of driver mutations that are functionally involved in tumor development. There are generally 40 to 100 genetic alterations that affect protein sequence in a typical cancer, although statistical analyses suggest that only 8–15 are functionally involved in tumorigenesis. The picture that


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InternalMed_Harrison. 40 to 100 genetic alterations that affect protein sequence in a typical cancer, although statistical analyses suggest that only 8–15 are functionally involved in tumorigenesis. The picture that emerges from these studies is that most genes found mutated in tumors are actually mutated at relatively low frequencies (<5%), whereas a small number of genes (such as p53, KRAS) are mutated in a large proportion of tumors (Fig. 101e-8). In the past, the focus of research has been on the frequently mutated genes, but it appears that the large number of genes that are infrequently mutated in cancer are major contributors to the cancer phenotype. Understanding the signaling pathways altered by mutations in these genes, as well as the functional relevance of these different mutations, represents the next challenge in the field. Moreover, a detailed knowledge of the genes altered in a particular tumor may allow for a new era of personalized treatment in cancer medicine (see below). A major effort


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InternalMed_Harrison. next challenge in the field. Moreover, a detailed knowledge of the genes altered in a particular tumor may allow for a new era of personalized treatment in cancer medicine (see below). A major effort in the United States, The Cancer Genome Atlas (http://cancergenome.nih.gov) is a coordinated effort from the National Cancer Institute and the National Human Genome


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InternalMed_Harrison. Prepare cDNA, label FIGURE 101e-7 A microarray experiment. RNA is prepared from cells, reverse transcribed to cDNA, and labeled with fluorescent dyes (typically green for normal cells and red for cancer cells). The fluorescent probes are mixed and hybridized to a cDNA array. Each spot on the array is an oligonucleotide (or cDNA fragment) that represents a different gene. The image is then captured with a fluorescence camera; red spots indicate higher expression in tumor cells compared with reference, while green spots represent the lower expression in tumor cells. Yellow signals indicate equal expression levels in normal and tumor specimens. After clustering analysis of multiple arrays, the results are typically represented graphically using a visualization software, which shows, for each sample, a color-coded representation of gene expression for every gene on the array.


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InternalMed_Harrison. Research Institute to systematically characterize the entire spectrum of genomic changes involved in human cancers. Similarly, COSMIC (Catalogue of Somatic Mutations in Cancer) is an initiative from the Welcome Trust Sanger Institute to store and display somatic mutation information and related details regarding human cancers (http:// cancer.sanger.ac.uk/). PERSONALIZED CANCER TREATMENT BASED ON MOLECULAR PROFILES: PRECISION THERAPY


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InternalMed_Harrison. Gene expression profiling and genomewide sequencing approaches have allowed for an unprecedented understanding of cancer at the molecular level. It has been suggested that individualized knowledge of pathways or genes deregulated in a given tumor (personalized genomics) may provide a guide for therapeutic options on the tumor, thus leading to personalized therapy (also called precision medicine). Because tumor behavior is highly heterogeneous, even within a tumor type, personalized information-based medicine will likely supplement or perhaps one day supplant the current histology-based therapy, especially in the case of tumors resistant to conventional therapeutic approaches. Molecular nosology has revealed similarities in tumors of diverse histotype. The success of this approach will be dependent on the identification of sufficient actionable changes (mutations or pathways that can be targeted with a specific drug). Examples of currently actionable changes include mutations in BRAF


InternalMed_Harrison

InternalMed_Harrison. dependent on the identification of sufficient actionable changes (mutations or pathways that can be targeted with a specific drug). Examples of currently actionable changes include mutations in BRAF (targeted by the drug vemurafenib) and RET (targeted by sunitinib and sorafenib), and ALK rearrangements (targeted by crizotinib). Interestingly, studies have reported that 20% of triple-negative breast cancers and 60% of lung cancers have potentially actionable genetic changes. Gene expression also offers the potential to predict drug sensitivities as well as provide prognostic information. Commercial diagnostic tests, such as Mammaprint and Oncotype DX for breast cancer, are available


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InternalMed_Harrison. FIGURE 101e-8 A two-dimensional maps of genes mutated in colorectal cancer. The two-dimensional landscape represents the positions of the RefSeq genes along the chromosomes and the height of the peaks represents the mutation frequency. On the top map, the taller peaks represent the genes that are commonly mutated in colon cancer, while the large number of smaller hills indicates the genes that are mutated at lower frequency. On the lower map, the mutations of two individual tumors are indicated. Note that there is little overlap between the mutated genes of the two colorectal tumors shown. These differences may represent the basis for the heterogeneity in terms of behavior and responsiveness to therapy observed in human cancer. (From LD Wood et al: Science 318:1108, 2007, with permission.) to help the patients and their physicians make treatment decisions. 101e-9 Personalized medicine is an exciting new avenue for cancer treatment based on matching the unique features of a tumor to an


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InternalMed_Harrison. to help the patients and their physicians make treatment decisions. 101e-9 Personalized medicine is an exciting new avenue for cancer treatment based on matching the unique features of a tumor to an effective therapy, and this concept is in the process of changing our approach to cancer therapy in fundamental ways. On a cautionary note, gene expression can vary enormously within a single person’s cancer and at different anatomic sites in the patient. We have not yet determined whether such clonal variation within an individual tumor will interfere with the goal tailoring therapy to a particular patient’s tumor.


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InternalMed_Harrison. A revolution in cancer genetics has occurred in the past 25 years. Identification of cancer genes has led to a deep understanding of the tumorigenesis process and has had important repercussions on all fields of cancer biology. In particular, the advancement of powerful techniques for genomewide expression profiling and mutation analyses has provided a detailed picture of the molecular defects present in individual tumors. Individualized treatment based on the specific genetic alterations within a given tumor has already become possible. Although these advances have not yet translated into overall changes in cancer prevention, prognosis, or treatment, it is expected that breakthroughs in these areas will continue to emerge and be applicable to an ever-increasing number of cancers. phenotypiC CharaCteristiCs of MaLignant CeLLs


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InternalMed_Harrison. phenotypiC CharaCteristiCs of MaLignant CeLLs Deregulated cell proliferation: Loss of function of negative growth regulators (tumor-suppressor genes, i.e., Rb, p53), and increased action of positive 102e Jeffrey W. Clark, Dan L. Longo growth regulators (oncogenes, i.e., Ras, Myc). Leads to aberrant cell cycle con- Cancers are characterized by unregulated cell division, avoidance of cell death, tissue invasion, and the ability to metastasize. A neoplasm is benign when it grows in an unregulated fashion without tissue invasion. The presence of unregulated growth and tissue invasion is characteristic of malignant neoplasms. Cancers are named based on their origin: those derived from epithelial tissue are called carcinomas, those derived from mesenchymal tissues are sarcomas, and those derived from hematopoietic tissue are leukemias, lymphomas, and plasma cell dyscrasias (including multiple myeloma).


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InternalMed_Harrison. Cancers nearly always arise as a consequence of genetic alterations, the vast majority of which begin in a single cell and therefore are monoclonal in origin. However, because a wide variety of genetic and epigenetic changes can occur in different cells within malignant tumors over time, most cancers are characterized by marked heterogeneity in the populations of cells. This heterogeneity significantly complicates the treatment of most cancers because it is likely that there are subsets of cells that will be resistant to therapy and will therefore survive and proliferate even if the majority of cells are killed.


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InternalMed_Harrison. A few cancers appear to, at least initially, be primarily driven by an alteration in a dominant gene that produces uncontrolled cell proliferation. Examples include chronic myeloid leukemia (abl), about half of melanomas (braf ), Burkitt’s lymphoma (c-myc), and subsets of lung adenocarcinomas (egfr, alk, ros1, and ret). The genes that can promote cell growth when altered are often called oncogenes. They were first identified as critical elements of viruses that cause animal tumors; it was subsequently found that the viral genes had normal counterparts with important functions in the cell and had been captured and mutated by viruses as they passed from host to host.


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InternalMed_Harrison. However, the vast majority of human cancers are characterized by a multiple-step process involving many genetic abnormalities, each of which contributes to the loss of control of cell proliferation and differentiation and the acquisition of capabilities, such as tissue invasion, the ability to metastasize, and angiogenesis. These properties are not found in the normal adult cell from which the tumor is derived. Indeed, normal cells have a large number of safeguards against uncontrolled proliferation and invasion. Many cancers go through recognizable steps of progressively more abnormal phenotypes: hyperplasia, to adenoma, to dysplasia, to carcinoma in situ, to invasive cancer with the ability to metastasize (Table 102e-1). For most cancers, these changes occur over a prolonged period of time, usually many years.


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InternalMed_Harrison. In most organs, only primitive undifferentiated cells are capable of proliferating and the cells lose the capacity to proliferate as they differentiate and acquire functional capability. The expansion of the primitive cells is linked to some functional need in the host through receptors that receive signals from the local environment or through hormonal and other influences delivered by the vascular supply. In the absence of such signals, the cells are at rest. The signals that keep the primitive cells at rest remain incompletely understood. These signals must be environmental, based on the observations that a regenerating liver stops growing when it has replaced the portion that has been surgically removed after partial hepatectomy and regenerating bone marrow stops growing when the peripheral blood counts return to normal. Cancer cells clearly have lost responsiveness to such controls and do not recognize when they have overgrown the niche normally occupied by the organ from which


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InternalMed_Harrison. blood counts return to normal. Cancer cells clearly have lost responsiveness to such controls and do not recognize when they have overgrown the niche normally occupied by the organ from which they are derived. A better understanding of the mechanisms of growth regulation is evolving.