WHAT IS BREAST CANCER?
Although we try to group diseases together to allow a better understanding of how they develop, progress, and how to treat them, breast cancers are likely almost asunique as the individual in which they grow. There are similarities, but each breast cancer has its own characteristicsand the individual’s response to her cancer is likely unique. This variability complicates treatment. We rely on the T,N, M classification that groups breast cancers by size, histological characteristics, lymph node involvement, metastatic spread and differentiation. We also analyze cancers for estrogen and progesterone receptor status to determine whether or not hormone blocking agents may be helpful. Her2 levels are measured since Her2 positive cancers can benefit from specific treatments that interfere with this protein.
Modern care is trying to tailor treatment to each woman and her cancer. More recently genetic classifications havebeen introduced. Genetic analyses such as Oncotype Dx ([i]) are being used to predict the likelihood that a treated cancer will recur, and whether or not the patient with a particular cancer will benefit from certainkinds of therapy. An additional classification has been added that evaluates the molecular foundation of the various breast cancers ([ii]).
Luminal A: These cancers are hormone receptor positive (estrogen and progesterone). They are Her2 negative and tend to have the more favorable outcomes with low rates of proliferation as measured by low levels of the protein Ki67.
Luminal B: Are similar to Luminal A, but may be Her2 positive with higher levels of proliferation as measured by Ki67.
Basal-like (Triplenegative): These cancers are hormone receptor negative as well as Her2 negative and have a worse prognosis. They are more common in women with a genetic predisposition(see below) as well as younger women.
Her2 enriched: These cancers are negative for estrogen and progesterone receptors, but are Her2 positive. They tend to have a worse prognosis, but often can be successfully treated with medications that interfere with the Her2 protein.
THE GENETIC BASIS OF BREAST CANCERS
Asnoted earlier, the chromosomes in the nuclei of our cells contain the computer-likecode needed to make the cell function. Chromosomes are comprised of 4 basicmolecules that make up DNA. When segments of the DNA molecules are “turned on”, the gene code is copied to"messenger RNA", and the messenger RNA leaves the cell nucleus andgoes into the cell “cytoplasm” where ribosomes “read” the code and, following the instructions, synthesize proteins. It is these molecules that are fundamental for cell functions. These proteins run the cell and can be secretedto circulate to other parts of the body to perform other functions needed tosustain life.
DNA can be damaged by ingested material (food, chemicals,etc.), inhaled material, or certain forms of radiation. DNA can also be altered, spontaneously,to form “mutations” that differ from the “normal” gene sothat when transcribed by the ribosomes, it does not form the correct codeleading to theproduction of abnormal proteins that can compromise normal cell functions. There are DNA repair mechanisms that can fix damaged DNA, but if the damage cannot be corrected, there are mechanisms that recognize this and cause the cell to die and be reabsorbed, a process knownas apoptosis. If the DNA is altered, and not corrected, and, if for some reason, the cell does not die, it is possible for the cell to continue to live in analtered state. Alterations in DNA(spontaneous or from external effects) may be harmless, but, if there is enough damage, or if the damage is to critical genes, the usual mechanisms that keep the cell behaving normaly can be lost. If the cell does not die, and normal cell function is lost, the cell may take on undesirable features. There are cellular mechanismsthat keep our cells doing the right things. For example, if you cut yourself, cells divide to repairthe wound, and when it is closed and cells contact other cell, cell division stops(contact inhibition). If DNA changes cause damage to these control mechanisms than the cell can lose normal controls and may begin to divide (proliferate) without stopping. Two cells may become 4, 4 become 8, 8 become16, and so on. If more new cells arecreated than die (cancer cells do die), the net result is a growing mass of cells that does not stop growing, and the proliferating cells becomes a “tumor”. If the tumor cells kill normal cells, and spreads to other parts of the body, then the tumor is “malignant” and is called a cancer.
GENETIC PREDISPOSITION TO BREAST CANCER
Most breast cancers are “statistical bad luck”. The longer we live the greater the chance that a cell in one of our organs acquires sufficient damage that is not corrected, and does not kill the cell, that it becomes a cancer cell and unimpeded proliferation begins. Since breastcancers likely begin many years before even the earliest ability to detect them, it is impossible to know what caused a particular cancer. Most breast cancers are “sporadic”. This means that we have no explanation as to how or why, or even when the cancer began.
One of the major reasons breast cancers develop is that the cell loses its ability to repair DNA damage. It appears that some damage to a cell is tolerated,and other damage leads to apoptosis, but loss of DNA repair greatly increasesthe risk of developing a breast cancer. This appears to be the reason why women who inherit ineffective (mutated) BRCA1 or BRCA2 genes have a very high risk of developing breast cancer. These appear to be repair genes, so losing them prevents a cell from repairing DNA damage.
All cells contain two copies of each gene and, hence two copies (alleles) of the DNA code. This provides significant protection from cancers. Even if one copy is damaged or lost, the cell can continue to functionusing its good copy. If the good copy is also lost or damaged, then problems occur. Women who inherit a faulty genetic allelethat normally helps to repair damaged DNA (BRCA genes) have an increased risk of developing breast or ovarian cancer. Since the problemfor these women is that the mutation is inherited, it is in every cell in the body. If both alleles are nonfunctioning, then the embryo fails. If only one allele is compromised, life develops, but the risk of canceris greatly increased. Again, since the normal allele can repair DNA damage, the cells function normally. It is only when a cell’s normal allele isdamaged that the cell, now with both alleles compromised, loses its ability torepair DNA damage. The problem likelyoccurs when the cell sustains damage or a mutation in a specific portion of agene that does not kill the cell and, since both copies of the repair gene nolonger function, the cell cannot repairthe damage. If the damage leads to uncontrolled proliferation, then a tumor results.
The first such genes that have been discovered were named BRCA1 and BRCA2 (standing for “Breast Cancer 1 and Breast Cancer2”). In women (and some men) who inherit faulty BRCA1 or BRCA2 genes an abnormal copy of these genes is present in all of the cells of the individual’sbody. The cells function normally because of the good copy, but if the good DNA copy is damaged, then the cell repair function for that cell is lost, and the cell is more likely todevelop into a cancer if other damage occurs that can not be repaired or apoptosis does not eliminate the cell.
Although the risk of developing breast cancer for women who inherit a BRCA1 or 2 mutation is very high, only approximately 10% of breast cancers occur in these women (they are less than 2% of the population). Most breast cancers are “sporadic”. They occur without warning and with no reasonfor their occurrence. We have identified other factors that increase a woman’s risk of developing breast cancer, but the vast majority of women who develop breast cancer each year do not have any of the major risk factors. This means that,at this time, there is no way of predicting who will get breast cancer, and noway of predicting who will not get breast cancer. Since 75% of women diagnosed each year havenone of the known elevators of risk, all women are at risk of developing breast cancer and, as will be discussed, all women should be offered screening.
DUCTAL CARCINOMA IN SITU(DCIS) AND LOBULAR CARCINOMA (LCIS)
It is likely (not certain) that most breast cancers begin as a single cell in the lining of a duct or lobule that is either damaged or mutates and begins to grow without the usual controls. This cell and its clones (other cells thatdevelop from it) grow with the characteristics of the first cell, but cancer cells tend to be genetically unstable and are prone to additional mutations and these can result over time in new clones with differing characteristics forming. It is rare, if ever, that a breast cancer is monoclonal. The fact that by the time we treat cancers they have likely been around for years means that they are polyclonal making it difficult to find a therapy that will destroy allthe cancer cells.
Because breast cancer appears to begin in the lining cells of the duct or lobule they have been named based on the appearance of the cancer cells as either of ductal or of lobular origin. As the cells proliferate they may remain inside the ducts or the lobules. They keep dividing and fill the ducts and lobules distending them and oozing up and down the branches, but they remain intra(within) ductal. Most of these appear to come from the lining cells of the duct and so they are given the latin description of "ductal carcinoma in situ" meaning "in the site of their origin" and providingthe acronym DCIS. Intraductal cancers cannot be lethal because,with no blood vessels or lymphatics inside the ducts, the cancer cells have no way to spread to other parts of the body leading to metastatic disease and ultimately death. Similarly, there are cancers thatappear similar to the lining cells of the lobule and, consequently,are called "lobular carcinoma insitu". These are likely artificial designations. Laszlo Tabar has questioned the underlying classification system, but they have been used for decades to classify cancers.
Although DCIS appears to be the precursor to invasive ductal carcinoma, and, invariably, when an invasive cancer arises it is in the same breast and location as the DCIS, LCIS seems to be more of a “high risk”lesion, and if a woman with LCIS develops a breast cancer it can be invasive lobular or invasive ductal, and the risk is similar in both breasts. For this reason, DCIS is treated locally as aprecursor lesion while women with LCIS are considered at higher risk, but are not treated and only followed carefully.
As the cells proliferate, intraductal cancer is contained in the duct by the tough tissue that surrounds the ducts called the "basement membrane". Since the cells continue to grow they must go somewhere. The pressure of the growing cells can cause the duct to distend, and cells move up and down the branches of the ductal tree like tooth paste. They can fill many branches and occupy a large part of the breast but may still remain trapped inside the duct system. Contrary to popular belief,breast cancer cells are not immortal. They die at a fairly high rate. Unfortunately, they multiply at a higher rate. It is the death of cells in the milk duct that can lead to calcium deposits where the cells died, and these calcium deposits can be seen on mammograms and lead to the detection of this earliest form of breast cancer.
DCIS cannot kill, but if they invade forming an infiltrating (invasive) carcinoma they gain access to the vascular system and the lymphatics and have the potential to metastasize.
INVASIVE BREAST CANCER
Although the actual sequence of events that leads to the development of a specific cancer cannot be ascertained, the available information suggests that the longer intraductal cancer is around and the larger the number of intraductal cancer cells that are present, and the less well differentiated the cells, the greater the chance that these cells will develop the ability to get through the basement membrane and spread into the tissue that surrounds the ducts. It is unclear what changes take place for an intraductal cancer to“invade” (break out of the duct) and “infiltrate” into the tissue surrounding the duct. It used to be thought that this was the result of additional DNA changes that "turned on" the cells ability to manufacture enzymes that would help it melt the basement membrane. More recent work suggests that it is more complicated. It may turn out that the cancer somehow recruits the normal cells around the duct to make invasion possible. This has not beende fined by researchers. It is the ability of cancer to invade that leads to the lethal potential of a breast cancer. It is when cancer cells spread to other parts of the body creating "metastases" that breast cancer becomes lethal. These metastatic lesions grow inother organs like the liver, bone marrow, lung or brain, and by destroying these organs, kill the individual.
Since all breast cancers start inside the duct system, by definition they all beginas "in situ" cancers. Thereis, however, a great deal of controversy about the importance of finding a breast cancer while it is still “in situ”. Autopsy studies have shown that some women, who die from other causes, have in situ breast cancer that never affected them during their lives. This has led some investigators to believe that many of these early cancers may never affect the individual in which theyare found. In the past, very few women were found with in situ breast cancer. Mammography, however, is very good at finding these lesions and because of mammography screening the detection of in situ breast cancer has increased dramatically. The problem is that there is no way, as yet, to tell which lesions will go on to become invasive breast cancers and which will remain in the duct, and be no threat to the patient. Some data suggest that if the in situ lesionis "high grade" - its cells look very aggressive under microscopic evaluation - that it will become invasive in a shorter period of time than if it is low grade (with intermediate grade in between)([iii]). My interpretation of the data agrees with this, but it is clear that even low grade DCIS, if given enough time, may progress to invasive and lethalbreast cancer ([iv]). Of course if a woman dies for some other reason before her breast cancer reaches a lethal level, then the breast cancer will have not been important for that particular woman. It is the uncertainties that have not been worked out that lead to doctors treating most breast cancers – intraductal as well as invasive – but this will likely be changing if we can better predictthe "bad actors". The hope is that a better understanding of the DNA changes associated with breast cancers will lead to a better prediction as to how they will behave, and more tailored treatment, or simply “watchful waiting” for cancers that have a low potential to kill.
Since the amount of time that DCIS is permitted to grow is likely important, age maybe an important criterion when it comes to in situ breast cancer since with age come “competing causes of morbidity and mortality”. DCIS in an 85 year old woman who may live another 5-10 years may nothave the same significance as DCIS in a 42 year old woman who may live another 40 or 50 years. We don't know the absolute risk of DCIS if left alone and undiagnosed. It may be as low as a 25% lifetime risk, or higher than 75% of progressing to an invasive breast cancer.
Confusing the issue still further is the fact that DCIS and Lobular Carcinoma in Situ (LCIS)have similar names, but seem to have differing importance. As noted earlier,when aninvasive breast cancer arises in a woman who has DCIS, the invasive cancer occurs in the same breast and in the same area where the DCIS had been found,and the invasive cancer looks like the DCIS. This suggests a direct relationship between DCIS and the invasive breast cancer. In a woman who has LCIS therelationship is much less clear. She hasa high risk of developing breast cancer, but the chance of it arising in the opposite breast is almost as high as for the breast in which it is found, andthe invasive cancer may look like it came from the cells of the duct as oftenas it looks like it came from the cells of the lobule.
It used to be thought that the risk of developing aninvasive cancer in a woman with known LCIS was equal for both breasts. New data suggests that LCIS is associatedwith an invasive breast cancer only about 5% of the time, but the old data suggested that a woman with LCIS had a 15% chance of developing an invasive cancer in thebreast containing the LCIS and 15% in the other breast for a total of a 30% riskof developing invasive breast cancer over the next 20 years. Because this is still a fairly low risk andboth breasts are at equal risk, most do not treat LCIS like a cancer, but viewit as a risk factor and carefully monitor the patient with LCIS with twiceyearly clinical examinations and annual mammography.
Hopefully,our understanding of DCIS and LCIS will be changing as we begin to understand the genetic causes of these cell changes.
Metastatic Cancer
Not only is the tumor capable of destroying cells that get in its way, but once a breast cancer breaks out of the duct the cells have the opportunity to cut their way into the blood vessels and lymphatic vessels that surround the duct. Blood vessels and lymphatics form conduits for cancers cells to float and spread to other parts of the body creating metastatic spread. It is met
