A Brief Outline of Prostate Cancer

Transcription

1 A Brief Outline of Prostate Cancer Assessment of Prognostic Factors to Assist in Therapeutic Choices Courtesy of Molecular Oncology International Introduction and Background Newer advances in the molecular understanding of cancer are giving us some new weapons (therapies) in the fight against this disease. Even more important are efforts to find the disease earlier. Given our current state of knowledge, early diagnosis is the most important advance of the century. Use of the PAP smear for early diagnosis of cervical cancer is the best example of this. More recently, with the advent of mammography and increased attention to breast self-examination, breast cancers are now being diagnosed much earlier than they were, even as recently as ten years ago. And now, serum PSA screening is doing the same thing for prostate cancer. In point of fact, it is likely that your cancer was discovered as a result of this test, or of diligent physical examinations by your physician. In the case of prostate cancer, however, this early diagnosis is a double-edged sword. Because prostate cancer is so often a very slowly growing cancer (more so than virtually any other type of cancer), many of the cancers being discovered today may need little or no therapy. The challenge is to determine which of the cancers are of this variety, which ones need curative therapy (because they are confined to the gland), and which ones need more aggressive therapy (because they have already escaped from the prostate gland at the time of diagnosis). On the other hand, we have not yet demonstrated that earlier diagnosis of prostate cancer will actually result in a net reduction in mortality due to the disease. Seems paradoxical, doesn t it? But this has not actually been proven for prostate cancer yet, because the use of PSA for early diagnosis has not been around for a long enough time to see what its effect on long term survival (15 years or more) actually is. We can only reason by analogy with breast cancer, where early diagnosis has resulted in a 30% decrease in mortality. The Problem of Staging The prostate gland is relatively inaccessible, which makes it very hard to learn what we need to know about a cancer in it, prior to removing it from the patient. This last phrase is the key, because the goal is to remove the prostate gland, if, and only if: 1) the tumor is sufficiently large and aggressive enough to threaten the life of the patient if it was left in, and 2) it is still confined to the gland itself and has not spread even a fraction of an inch outside the gland. The reason for this is that surgical removal of the cancer is curative only if it removes all of the tumor. If the gland is removed, thinking that the tumor is confined to the gland, and then we find on detailed pathological examination (this is done after the surgery) that it penetrates the capsule, or has migrated to the seminal vesicles, or even to regional lymph nodes, then we have given the patient too much therapy in terms of local surgery, and further systemic therapy must also be added. Similarly, if we remove the gland, and find that it is very small (less than the size of a cube of sugar), then again we have done too much surgery, because the high likelihood is that this tumor would not grow large enough in the patient s lifetime to cause any serious injury. The catch 22 is that there is no absolute way to make this determination without actually taking the gland out. The best we can do is to calculate the probability that the tumor is confined to the prostate, based on a series of tests we will describe in this paper. But before we describe these tests, I think it will be useful to outline for you what is known today about the origins, growth and evolution of cancers in general, and prostate cancer in particular.

2 Initiation of Cancer We now know that cancer is a genetic disease. By this, we mean that the root causes of the disease are alterations in some of the genes in the nuclei of the cell. The vast majority of these alterations (mutations) are what we call somatic mutations, that is to say, they happen during the lifespan of the individual, and die with the individual; they are not inherited. (There are a few cancer-producing mutations that are inherited, and they are gaining much publicity today, but we will not be concerned with them in this booklet.) We also know that several mutations are required to produce a cell that has the characteristics of cancer; one is not enough. DNA Repair Normal cells have to replace themselves periodically, which means that they must duplicate their entire DNA complement. During this duplication process, there is a small but finite chance that a mistake will be made in copying the DNA, i.e., a mutation will occur, just because the DNA replication process is not perfect. But nature has provided us with a mechanism to protect against these mistakes. We have several enzymes in our nuclei that have the ability to recognize when new DNA has a mistake in it, and to correct the mistake. These are termed DNA repair enzymes. They are like little watchdogs, constantly surveying the genome (word for the entire complement of DNA), looking for mistakes that occur in duplication, or as a result of agents in our environment that can cause mutations even in non-dividing cells, and then patching up the error. The earliest mutations leading to cancer most probably involve the DNA that codes for the critical enzymes involved in DNA repair, because with these mechanisms hampered, the cell is much more liable to subsequent mutations in any part of the genome. That is to say, any subsequent mutations are the less likely to be corrected, and thus to stay with the cell for the lifetime of the individual. The later mutations that are often found in cancer cells are usually in genes that control house-keeping functions of the cell, such as regulation of cell division, intracellular communication and response to external stimuli. Thus we find mutations in tumor suppressor genes, which turn out to be genes that are critical in slowing down the rate of cell division. Examples are p53 and the retinoblastoma gene, both of which normally cause cycling cells to hesitate in cell division, probably so that the DNA repair enzymes can have time to correct any mistakes that have been made in the process of duplicating the genome. If these enzymes (either or both the DNA repair genes and the cell cycle regulating genes) are mutated and non-functional, many mistakes will not be corrected; more mutations can be propagated, accumulating as the cell continues to proliferate. There is another class of genes that is important in carcinogenesis the oncogenes. These, when mutated, generally result in a gain of function (mutations in the DNA repair enzymes and tumor suppressor genes cause a loss of function). Most of the oncogenes are involved with intracellular and intercellular communication, and when they are mutated, it is as if some aspect of cellular communication is stuck in the on position. Examples of these include a host of growth factors and their receptors, e.g., epidermal growth factor receptor (also known as erbb1), its second cousin erbb-2 (also known as HER-2, or neu), transforming growth factors alpha and beta, the ras oncogene, the src oncogene, etc., etc. The bottom line is that cells that develop mutations in one or more of these oncogenes become less responsive to the subtle messages they receive from their extracellular milieu. It s like they become deaf, or their telephone lines are cut. They go on, blithely unaware of messages that are telling them to alter their function. This translates to the phenomenon of autonomy, a characteristic that has long been associated with neoplastic cells. Yet another oncogene, bcl-2, normally regulates the elimination of cells that are genetically too unstable to function properly in the organism. This occurs through a process termed programmed cell death, or apoptosis. The p53 gene is also connected to this process, in that a normally functioning p53 molecule will send cells which are unable to be repaired, to the apoptotic process. If all of these mutations occur, we now have a clone of cells that is programmed to be genetically unstable (decrease in DNA repair activity), to lack brakes on the cell division process, (altered tumor suppressor gene) and not to respond normally to stimuli that ordinarily modulate the function of the cells (mutations in oncogenes). And if the bcl-2 oncogene is not functioning properly, then fewer cells will die than is normal, i.e., the cells will continue to accumulate inexorably. Basically, they have become immortal, yet another characteristic of cancer cells that has been recognized for some time.

3 We can get a much better idea of how to treat the tumor if we know the answers to some or all of these questions. This is the job of prognostic tests. Pathologists and urologists have always sought this type of information, and several tests have been in use for many years. We will recount these, and will go on from there to de- It is likely that many clones of cells attain this stage of evolution; however, if they grow to a size of 1 mm diameter or so, they will no longer be able to survive, because they rely upon diffusion to gain nourishment from the extracellular fluid. Tumors that do survive develop the ability to stimulate the growth of new capillaries into the tumor, a process termed angiogenesis. This process is extremely complex, and depends upon an interplay among several molecules that have facilitatory and inhibitory influences on the proliferation of endothelial cells (those cells lining the walls of blood vessels). Suffice to say, if a tumor is going to survive, either as a primary tumor or as a metastatic deposit in another part of the body, it must develop the ability to generate new vessels to nourish itself. Thus, you can see that the process of carcinogenesis is a multi-step process; it generally requires several years to get to a size large enough to be detected. Invasion and Metastasis Invasion = movement of a tumor into adjacent tissues Metastasis = spread of a tumor to distant site(s) in the body All of the above mechanisms deal with the growth and survival of a tumor population, but do not address the phenomenon that is responsible for death of the patient. We speak of metastasis as being responsible for death, but I think it is really just a means to an end. What metastasis does is to provide a mechanism for tumor cells to proliferate to the point that the tumor burden eventually becomes too great for the patient to support. It gives the tumor more places in the body to grow. Angiogenesis allows a tumor deposit to grow to a size considerably larger than 1 mm diameter, but only to a point. A single tumor mass of any substantial size, say greater than 10 cm diameter, generally can no longer be supported even by the new vessels that grow in the process of angiogenesis. Large tumors have a lot of dead material in them, and cannot get much larger without losing parts of themselves. Thus, a solitary tumor has an upper size limit, even if all these new blood vessels supply it. The process of metastasis allows one to have many such masses, and once they are established, the geometric nature of tumor growth dictates that the late stages of cancer growth will increase the tumor burden dramatically in the last few weeks to months of the patient s life. We speak of tumor doubling times, and the work that has been done in this area suggests that prostate cancers have doubling times of up to four years. By the time a tumor is 1-2 mm in diameter, and is theoretically discoverable, it has undergone about doublings. Without intervention, only about more doublings are required to overwhelm the patient and result in death. This is not much of a problem if the patient is already 80 years old and has a tumor with a doubling time of 4 years. But a 50 year old with a tumor doubling time of six months is in trouble. To summarize thus far, you can see that there are several things that are important to know about prostate cancer when deciding how to treat it. These include: The age of the patient The doubling time of the tumor The size of the tumor at the time of diagnosis How far along in its evolution is it when discovered? How aggressive is it? Is it organ-confined, or has it escaped the confines of the prostate gland? Has it spread to distant sites? Last, and certainly not least, what form(s) of therapy are desired by the patient? Predictive (Prognostic) Tests

4 tail some of the more sophisticated tests based on newer concepts of tumor and molecular biology. Clinical Stage Staging of a tumor refers to the state of the tumor at the time of diagnosis, particularly in reference to its localization to its primary site vs. spread to adjacent or distant organs. There are two types of staging: 1) clinical and 2) pathological. Clinical staging is what can be determined before the tumor has been removed for pathological evaluation, and pathological staging refers to staging after pathological evaluation. The latter is more accurate, but less useful to the patient, because the tumor is already out when it can be determined. Clinical staging is what the urologist must use in devising therapeutic options, but is less accurate, because (especially in the prostate) critical distinctions in staging depend upon close evaluation of the gland itself, and cannot be determined accurately without taking the gland out. Catch 22. Nevertheless, clinical staging is very important in determining prognosis and in devising therapeutic options. The most commonly used staging system is the TNM system. T stands for tumor, N stands for lymph node status, and M stands for distant metastases. Each of these letters is accompanied by a number (1,2 ), each of which may also be subdivided with small letters (a,b ). The following gives examples of the system. T1 means the tumor is not palpable or visible by imaging techniques (ultrasound) T1a = discovered incidentally (as by transurethral resection of BPH) and occupies 5% or less of the tissue examined T1b = discovered incidentally and occupies more than 5% of the tissue examined T1c = discovered by needle biopsy (e.g., because of elevated PSA) T2 means that the tumor is thought to be confined to the prostate gland T2a = tumor involves only half of a lobe or less T2b = involves more than half a lobe, but not both lobes T2c = tumor involves both lobes T3 means that the tumor extends through the prostatic capsule T3a = capsular extension on one side only T3b = bilateral capsular extension T3c = tumor invades seminal vesicle(s) T4 means that the tumor is fixed to or invades adjacent structures other than the seminal vesicles T4a = tumor invades any of: bladder neck, external sphincter or rectum T4b = tumor invades pelvic floor muscles and/or is fixed to the pelvic wall N0 = No regional lymph node metastasis N1 = Metastasis to a single lymph node M0 = No distant metastases M1 = Distant metastases M1a = Lymph nodes away from the pelvis M1b = Metastases to bone(s) Histological Grade

5 We have come to recognize, under the microscope, that normal cells are organized into tissues and organs in a systematic, recognizable order, and that the cells of any given tissue look pretty much alike. Cells making up cancerous tissues bear some resemblance to the normal cells, but also assume a range of disorder that makes them less recognizable as belonging to the type of tissue from which they arose. The degree to which cancerous cells resemble their normal cells of origin is termed differentiation. A tumor is well differentiated if it closely resembles the normal cells, and poorly differentiated if it bears little resemblance to the normal cells. It is well established that poorly differentiated tumors behave more aggressively than well-differentiated ones. There have been several classification systems developed to measure the degree of differentiation, but the one in most common use in the prostate gland is the Gleason system. The Gleason system divides the level of differentiation into five levels, numbered from one to five, going from well to poorly differentiated. It also takes into account a common phenomenon in prostate cancer that one often finds portions of the cancer that have different levels of differentiation. Therefore, Gleason proposed that we account for this in the grading scheme by listing the two most prevalent levels of differentiation in the tumor, and adding them together to produce a Gleason Score. Thus, a tumor with grades of differentiation of two and three would have a Gleason Score of five; one with grades of three and five would have a Gleason Score of eight, etc. The following table lists several features that we know about tumors with various Gleason Scores. Gleason Score = 2,3, or 4 5,6, or 7 8,9, or 10 Degree of differentiation Well Moderate Poor Probability of spread Low Intermediate High How many tumors are: 25% 60% 35% You can see that, based on the Gleason Score alone, one can get a first approximation of how aggressive the tumor is expected to be, and thus, how you might want to treat it. The Gleason system was created by examining prostate glands after they were totally removed, and the entire cancer was available for evaluation. When we apply the Gleason system to needle core biopsies of the prostate, we have not sampled the entire tumor, and there may be areas in the tumors that are different from what we found in the biopsy sample. This means that the Gleason Score applied to needle cores is only a predictor of what the entire tumor may show, and thus has a degree of sampling error that is impossible to avoid. Current practice of taking six separate needle cores is an attempt to minimize this sampling error. The second drawback of any grading system is that it does not predict with 100% accuracy the probability of spread. Well-differentiated tumors, while having a low probability of spread, do not have a 0% probability. And poorly differentiated tumors, while having a high probability of spread, do not have a 100% probability. Given that, the biggest problem comes with the moderately differentiated group, because the likelihood of spread in that group is about 50%, which is unacceptable in terms of making therapeutic decisions. It would be like flipping a coin to determine whether or not to take out your prostate gland. A third drawback of using only a grading system to predict behavior can be illustrated as follows. Well differentiated tumors tend to be smaller in volume and slower growing; some of them are so small and slowly growing that they will not become large enough to cause any clinical problems before the patient ages enough to die of other natural causes. It makes little sense to treat such cancers aggressively, as the treatment would be much more harrowing than the disease. We term these cancers latent or incidental. But, some of the welldifferentiated tumors are larger and more rapidly growing, and very likely would spread, if not removed or treated. Clearly we want to get rid of these tumors, so that later complications are avoided. Since the grading system cannot predict these circumstances completely, we have developed other means of predicting tumor behavior, to use in combination with the grading system.

6 Tumor suppressor genes, as you will recall, are involved in regulation of cell division; mutations in these genes usually result in taking the brakes off of cell division, so that cells containing these mutations are favored to proliferate rapidly. Of several tumor suppressor genes discovered thus far, only one has been shown to have clinical relevance in prostate cancers. In the prostate, p53 has been shown to be a mutation that shows up rela- Perineural invasion Close inspection of all parts of tumor in needle core biopsies will occasionally reveal the presence of tumor nests in or immediately adjacent to tiny nerve filaments within the tissue. If this finding is present, there is a very high probability that the tumor has spread beyond the confines of the gland. Many of the nerve bundles that we see in needle cores are actually outside of the capsule of the gland, and so presence of tumor next to them documents extracapsular spread. But even if the nerve filament is within the prostate, we know that the nerves must get there from outside the capsule, and that where they penetrate the capsule comprises a weak point through which tumor cells can migrate. Therefore, we take pains to look closely for this finding, and comment about it in our report. It should be emphasized that not finding nerve filaments or perineural invasion does not eliminate the possibility that it may be there in other parts of the tumor not sampled. But if perineural invasion is found, there is a 96% chance that the tumor has escaped from the gland. Amount of tumor present in sextant core biopsies By carefully measuring the length of the biopsies and noting the amount of tumor in each, we can make a prediction of how much tumor is present in the gland. By coupling this measurement with the percentage of tumor that has a Gleason grade of four or five, we can refine that estimate. And by further taking note of the pattern of abnormality found on the ultrasound examination, equations have been constructed that can give us an even better estimate. The results predict whether a tumor is less than 0.5 to 1.0 cc (and is therefore likely a latent or incidental tumor), whether it is greater than 12 cc (and is therefore likely to have spread outside of the prostate), or whether it is somewhere in between (and therefore, other things being favorable, a candidate for prostatectomy). This method also has drawbacks. If the tumor has arisen deep within the prostate, the equations don t work (most tumors arise at the posterior periphery of the gland). And if the ultrasound does not clearly identify the tumor (this is termed isoechoic in medical doublespeak), the method does not work. It is also necessary for the ultrasound examination to be done with greater precision than a routine examination in order for this estimate to work satisfactorily. As an additional approximation of tumor volume, the method is useful for a majority of tumors. Partin Tables Allan Partin at Johns Hopkins University School of Medicine, has taken certain data, and constructed equations that predict several important aspects of prostate cancers. These include: Probability of tumor confinement to the prostate gland Probability of penetration of the tumor through the prostate capsule Probability of involvement of the seminal vesicle Probability of metastasis to regional lymph nodes The data he used are readily available, and include the Gleason Score, the serum PSA level and the clinical stage of the tumor at diagnosis. In order for prostatectomy to be most effective, the tumor must be confined to the prostate, and of a size between 1 and 12 cc. However, the larger the size, even when it is less than 12 cc., the more likely it is no longer confined to the gland. Newer Molecular Tests Tumor Suppressor Genes

7 tively late in the evolution of cancer. Thus, when a test for p53 mutation turns up positive, it is an ominous sign that the tumor is relatively advanced, and may well have spread beyond the confines of the gland. Cell Adhesion Molecules E-Cadherin and a closely associated molecule, alpha catenin, function normally to hold prostate epithelial cells together. If one or the other of them is altered or lost, the bonds that hold the epithelial cells together are broken, and theoretically the cells can drift apart. This is one of the features of invasive cancer cells. When a test for E- cadherin or alpha catenin shows one or the other to be lost, this is taken as evidence that the tumor has gained the potential to invade and metastasize, and therefore the probability that the tumor has spread beyond the capsule is greater. The test for either of these molecules is reported as presence or absence of the molecule, and if absent, whether it is uniformly absent or focally absent. Presence is taken to indicate a good prognosis. Angiogenesis Judah Folkman and his collaborators have shown that many different cancers require the ingrowth of new blood vessels in order to grow to a size of greater than 1 mm in diameter. This means that virtually any tumor that is discovered clinically has already attained the ability to induce the development of these new vessels (it is virtually impossible to detect tumors less than 2 mm in diameter clinically). However, if one measures the density of these new blood vessels in and around the tumor, those tumors with a greater density of blood vessels turn out to have a worse prognosis than those with only a few new vessels. Therefore, we have developed a way to count new blood vessels around any cancer, prostate included. The prognostic report gives you the result of this analysis, expressed as number of vessels per square mm of tumor, and indicates whether this number is in the lower, middle or upper third of values seen in our laboratory. This is the standard method of reporting this test, and corresponds to a good, intermediate or poor prognosis, respectively. It can be coupled with other prognostic factors to increase the accuracy of each of them taken individually. DNA content As a tumor evolves, its DNA becomes more and more laden with mutations of all kinds. By the time it is discovered, it may have so many mutations that the absolute quantity of DNA is actually abnormal (usually increased, but it may occasionally be decreased). We express the quantity of DNA in a tumor as a number, termed the diploid index, which is the amount of DNA in the tumor cells divided by the amount of DNA in normal cells. Thus, a tumor with 20% more DNA than normal would have a diploid index (DI) of 1.2. If the DI is less than 1.0, or is greater than 1.2, the probability of spread beyond the capsule is significantly higher. It has also been shown that a tumor with a diploid index of 1.0 is more likely to respond to total androgen blockade therapy than one with abnormal DNA content. As with Gleason scoring, we have to deal with sampling error when interpreting DNA content data. Finding only diploid DNA content in needle biopsies does not rule out the possibility that portions of the tumor not sampled harbor cells with abnormal DNA content. Therefore, finding only diploid DNA content is not as meaningful as finding abnormal DNA content, though the latter is more ominous in its meaning. Rate of cell proliferation It seems intuitively obvious that a tumor that has a higher proportion of its cells in the process of cell division would grow faster than a tumor with a low proportion of cells in the process of dividing. It would have a shorter doubling time (the time necessary for a tumor to double its size). An extraordinary amount of work has gone into documenting this obvious fact in several tumor systems (breast, melanoma, colon, etc.). However, the relationship between the proliferation index (proportion of cells in the process of dividing) and prognosis in prostate cancer is not as strong as it is in other organs. Perhaps this relates to the overall slower growth rate usually seen in prostate cancers, but we really don t know why this relationship is not strong in the prostate. Nonetheless, we do provide a measure of this parameter, which we do by measuring a molecule, called Ki-67. Ki-67 is a protein that is present in the nucleus of dividing cells, but is not present in non-dividing cells. We express the result as a

8 percent, meaning the percent of tumor cells that contain the Ki-67 molecule. We believe that the higher the percent of cells expressing Ki-67, the faster the growth rate, and the worse the prognosis. You should know, however, that the clinical evidence supporting that belief is weak. An Additional Critical Factor After considering all or some of these tests, you may still be left with less than 100% certainty regarding the choice of therapy. This discussion has been presented in order for you to have as much data as possible when making a decision about therapy. However, different people have different feelings about cancer and therapies. Some people simply want to be rid of the tumor, no matter what. They have a dread of the disease that surpasses all the logic they and we might bring to bear about the decision. Others are more concerned about side effects of the therapy that might be selected, whether the therapy is surgical, radiation or hormonal. It is important that you select a form of therapy that is congruent with your own feelings in the matter. Many of us men have difficult identifying our feelings, so it may not be easy to bring this aspect of the situation to bear on the decision. But I encourage you to reflect seriously on this part of the problem, because it will connect with who you really are at a deep level, and may very well influence how you respond to whatever form of therapy you ultimately choose.