LESSON 5.2 WORKBOOK. What do cancer screens really tell us? Workbook Lesson 5.2

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1 Mortality rate The rate at which people die from a specific cancer. For a complete list of defined terms, see the Glossary. LESSON 5.2 WORKBOOK What do cancer screens really tell us? Treating cancer successfully requires that we are able to detect it early. As more diagnostic techniques are developed it becomes important to understand how reliable they are how many cancers will they miss and how many times will they indicate that cancer is present when it is not? This lesson discusses the concepts of sensitivity and specificity and shows how screens can lead to overdiagnosis and why overdiagnosis poses a problem, using recent findings with breast and prostate cancers as an example. Evaluating cancer screens: specificity and sensitivity As we have discussed in previous lessons, an abiding problem with cancer treatment is that symptoms may appear well after the primary cancer has metastasize When this happens it is almost inevitable that the cancer has become more difficult, even too difficult to treat. It is clear that reliable screens to help us identify those benign tumors that are going to become malignant and malignant tumors before they metastasize are key. In the last lesson we began to examine the screening programs that are available to identify tumors at these early stages. But in order to evaluate how useful a screening program may be we need to have more information than how it works. We need to know whether it is effective in detecting tumors at the important stages before metastasis and whether it targets tumors for treatment that would never have been problemati These kinds of evaluation pose another problem the difference between population statistics and individual behavior. When a program is evaluated on the basis of its effectiveness for the population as a whole it gives no information to an individual as to how they themselves might fare. Sometimes an individual may fare in the same way as most of the population. Other times they may act like outliers and have an experience very different from the population as a whole. This is another challenge that we need to deal with when assessing which screens and treatments are most effective. Notes: 153

Specificity how accurate a screen is in identifying abnormal cells. False negatives Those cells (or people) that are abnormal, but are falsely identified as being normal.

2 Specificity how accurate a screen is in identifying abnormal cells. False negatives Those cells (or people) that are abnormal, but are falsely identified as being normal. Sensitivity how likely a screen is identify abnormal cells. False positives Those cells (or people) that are normal, but are falsely identified as being abnormal. Let s assume we are evaluating two screens that have been designed, like the Pap smear, to detect pre-cancerous and malignant cells. Let s say one screen detects the abnormal cells by dying a protein in the cells red, while the second screen detects abnormal cells by their shape. We evaluate the screens using two criteri The specificity of a screen tells us how accurate the screen Figure 1: Two sample screens for a population. A highly specific screen (Screen 1) will only identify diseased individuals, but may miss people who are diseased that do not test positive for the screen. A highly sensitive screen (Screen 2) will identify everyone with the disease, but may falsely identify some people as having disease that actually don t. is in identifying abnormal cells. The red screen would be good at identifying cells that are red, but will miss cells that are abnormal - if they aren t strongly red for example. These cells will be called false negatives ; that is, they are abnormal, but the screen hasn t detected them. On the other hand the sensitivity of a screen tells us how likely the screen is to identify abnormal cells. A cell shape screen will identify cells that are clearly abnormal well, but it may be more likely to define cells as abnormal that are really normal. These cells will be called false positives. Figure 1 compares how two different screens on a population of people some of whom are normal (green smiley faces) and some of whom are sick (orange sad faces). Screen 1 is in purple. Out of the 10 people in the population it has correctly identified 20% as sick and correctly identified all the normal people. However it has missed 20% of the population. These false negatives are sick but think they re normal. Screen 2 is in re Out of the 10 people in the population it has detected everyone who is sick, but it has also identified 30% of the normal population as sick These false positives are really normal. In reality all screens struggle to achieve the right balance between false negatives and positives but what is right? 1. According to Figure 1, how many people are false positives detected by Screen 2? 20%. 30%. 70%. 80%. 2. True or False: The best screens will have no false positives and no false negatives 154

Non-progressing cancers cancers that have evolved such that they can no longer grow or spread to other tissues. These cancers will not cause disease.

3 Non-progressing cancers cancers that have evolved such that they can no longer grow or spread to other tissues. These cancers will not cause disease. Overdiagnosis of cancer diagnosis of cancer that will never be life-threatening. Screening outcomes: the problem of overdiagnosis Figure 2: Model for progression of abnormal (cancer) cells. Fast growing tumors will be likely to cause disease and death from cancers, while patients with slow growing tumors and non-progressing tumors will likely die from unrelated causes before they will die from cancer. One important take-home message from this module is that cancer is the end-point of an evolutionary process that starts with a normal cell becoming able to hyperproliferate and ends with metastases. But there is no single path from benign to malignant and metastati Figure 1 illustrates four distinct ways the disease could progress from an initial screen (indicated by the abnormal cell in the bottom left. In the 1st model very fast the cancers progresses very quickly. Individuals will likely display symptoms very quickly after the cancer has been detected and are likely to die if they are not treate Clearly they would suffer greatly if they were a false negative on the screen, as would individuals in the 2nd model fast. On the other hand, in the 3rd model slow and the 4th model nonprogressing the cancer is growing so slowly that they will more likely to die from unrelated causes (like age) than they will from the cancer itself. This group would not suffer physically at all if their cancer was never identifie Not only that they will also be spared considerable non-productive anxiety over the years. The $64,000 question an informed patient would want answered is: Before I get tested how can you tell which model my cancer would fall under if it was detected?. It should be very clear from this module that we are still nowhere near having an answer to that critical question. Because of this the strategy that has been used is to screen and treat all cancers as though they fall into the worst case scenario that is if a screen detects evidence of a benign tumor, treat it as if it will become malignant, if it detects evidence of a malignant tumor treat it as if it will metastasize. This strategy would be appropriate for Models 1 and 2, but not for Models 3 and 4. The problem it causes has been termed overdiagnosis. Overdiagnosis then results in overtreatment. We can easily understand why overtreatment is problematic simply by knowing that the three major cancer treatments we have available, namely surgery, radiation, and chemotherapy are commonly referred to as slash, burn, and poison. Because cancer treatments themselves are so painful and traumatic, the decisions to treat when it is not required should not be taken lightly.. 3. True or False: All cancers will progress to metastasis. 155

4 US Preventative Services Task Force (USPSTF) a governmental agency responsible for determining guidelines for screening programs for the population. Prostate-specific antigen a protein that is produced by prostate cancer cells that is secreted into the bloo This protein has been used as a diagnostic test for prostate cancer. Cancer overdiagnosis and overtreatment Breast Cancer Mammograms have been used as routine screens for detection of breast tumors since the 1980s. Programs to raise awareness of breast cancer have promoted the notion that early detection is the key to a cure for breast cancer. And the best method for early detection was a yearly mammogram for every woman over the age of 40. Recently, the US Preventative Services Task Force (USPSTF), a governmental agency charged with determining the guidelines for screening programs throughout the country, changed these recommendations. Now mammograms are only recommended for women over the age of 50 and then only every 1-2 years, not necessarily annually. Figure 3: Since mammograms were introduced as routine screens in the 70s, there has been a rise in detected cancer, but this rise has not increased in a rise of late stage cancers. We are identifying many more cancers, but these may never become problemati These changes left many people perplexe What had happened? Was early detection no longer the key to cure? In fact the USPSTF report provided good evidence that the original mammogram screening program had detected many more early stage breast tumors and cancers (which is why the blue line in Figure 1 rises). However this increased detection hadn t improved the rate at which late stage cancers were diagnosed (the brown line in Figure 1 stays flat). Why not? The problem comes in connecting detection with cure. The USPSTF realized that most of the early stage tumors the mammogram screening program was detecting would never become the late stage aggressive metastatic cancers that cause severe disease (if they did the brown line in Figure 1 would fall). So, the screens were actually overdiagnosing cancer, by identifying women under age 50 who had malignant tumors in the Model 3 and Model 4 category. Many of those women were often also overtreated with extensive surgeries leading to extreme anxiety. 4. Overdiagnosis is a problem because: (Circle all correct.) Screens will falsely identify people with cancer who don t have disease. People don t need to know if they have cancer. Cancer treatment is so painful and traumati Some cancers will not ever metastasize and cause severe symptoms. 5. Why did the USPSTF change recommendations for mammograms? (Circle all correct.) They were trying to reduce overdiagnosis of breast cancer. Mammograms are unaffordable under most health care plans. The identification of late stage cancer was not being reduced by mammogram screenings. Early stage cancers were not being identified early enough. 6. True or False: Screening recommendations for the population are always under review. 156

5 Double mastectomy surgical removal of both breasts. Prostate Cancer Prostate cancer is extremely common it has been estimated that 80% of men over the age of 80 have a prostate cancer diagnosis. The early detection, early cure principle pushed for development of a routine screen. The prostate gland supplies the fluid for semen, and produces a protein called prostate-specific antigen (PSA), which promotes sperm movement. The prostate normally secretes low levels of PSA into the bloo Whenever the prostate is damaged, the secreted PSA levels in the blood rise. This is particularly true when prostate cells are hyperproliferating. Because of this, men over the age of 50 were recommended to have regular screens for blood PSA levels. If levels were high they were recommended for either surgery or radiation. Both of these treatment options are highly unpleasant. Because of the location of the prostate close to the urinary tract and genitals surgery commonly left men incontinent or impotent or both. Recently these recommendations have also changed and the USPSTF now no longer recommends PSA screens at all. Why? Two main reasons: First, prostate glands increase secretion of PSA whenever they are damaged, not just during cancer and many men, particularly aging men have high levels of PSA for other reasons such as because the prostate is inflame Second even though prostate cancer might be present and correlated with high PSA levels, this does not necessarily mean that a cancer will progress. In fact most prostate cancers fall solidly in Model 4 they never progress to severe disease. The recommended approach now is watchful waiting. The physician will regularly monitor a prostate tumor and only perform surgery or radiation treatment when there is evidence it is growing. Genetic Screens Cancer research has pinpointed mutations in several genes that are hallmarks for cancer. Individuals having these mutations may be predisposed to developing cancer since their cells are already on the way to becoming able to hyperproliferate. In particular certain combinations of mutations have clearly been associated with increased incidence (mutations to both BRCA 1 and 2 for example predispose to both breast and ovarian cancer). Angelina Jolie inherited both BRCA mutations and chose to have prophylactic surgery - she underwent a double mastectomy thereby reducing her risk of developing breast cancer by over 90%. However single mutations may never progress to cancer formation, and hence prophylactic surgery in this case is likely to be overtreatment. As we ve described in this module, it takes many steps for a tumor to become a cancer, and we are not able to predict what path any once cell will take. While some people might favor life-altering cancer treatment under any conditions, others might alter their treatment plan if they understand when receiving a diagnosis of cancer does not necessarily meant developing a life-threatening disease. Individual health choices may vary from what the USPSTF recommends, but it is important that these choices are made through informed decisions. 7. Which of the following is a reason that PSA screens are not recommended for prostate cancer? (Circle all correct.) The PSA test is not very accurate in identifying PSA levels. Prostate cancer is a slowgrowing disease. Many people have high blood PSA levels normally. PSA is secreted non-specifically. 8. True or false: A genetic screen of your DNA sequence will reduce your risk of cancer overdiagnosis. 157

6 STUDENT RESPONSES Explain how specificity and sensitivity are a trade-off in cancer screens. Also, what instances would you want a highly specific cancer screen? When would you want a highly sensitive cancer screen? (Hint think about severity of disease vs. severity of treatment.) Remember to identify your sources 158

7 TERMS For a complete list of defined terms, see the Glossary. TERM Double mastectomy False negatives False positive Non-progressing cancers Overdiagnosis of cancer Prostate-specific antigen Sensitivity Specificity US Preventative Services Task Force (USPSTF) DEFINITION Surgical removal of both breasts. Those cells (or people) that are abnormal, but are falsely identified as being normal. Those cells (or people) that are normal, but are falsely identified as being abnormal. Cancers that have evolved such that they can no longer grow or spread to other tissues. These cancers will not cause disease. Diagnosis of cancer that will never be life-threatening. A protein that is produced by prostate cancer cells that is secreted into the bloo This protein has been used as a diagnostic test for prostate cancer. How likely a screen is identify abnormal cells. How accurate a screen is in identifying abnormal cells (or people). A governmental agency responsible for determining guidelines for screening programs for the population. 159

Let s look a minute at the evidence supporting current cancer screening recommendations.

Let s look a minute at the evidence supporting current cancer screening recommendations. I m Dr. Therese Bevers, Medical Director of the Cancer Prevention Center and Professor of Clinical Cancer Prevention at The University of Texas MD Anderson Cancer Center. Today s lecture is on screening