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# DOUBLING TIME

A tumor consists of some normal tissue plus cancer cells that are descendants of one cell that had undergone a malignant transformation. The number of cells is described by the equation 2n where n is the number of doublings that have taken place. Tissue density is approximately a billion cells per cubic centimeter (cc). A billion is approximately 2 30. Ignoring the normal cells, a 1 cc tumor started as a single cancer cell that has divided 30 times. Data show the time for a breast cancer to double in volume is 25 days to at least 1000 days with a typical value of about 100 days. Depending on breast tissue density and structure, mammography is usually capable of finding breast tumors at approximately 1 cc. Combining this information, we can estimate the usual preclinical time of breast cancer as 30 doublings at 100 day doubling time or a total of 8 years. If left untreated, a primary breast cancer 1 liter (1000 cc) in size is typically lethal. That size is 40 doublings of a single cell. Thus the possible observation times in breast cancer is limited to between the 30th and 40th doublings or at most only the last 25% of the growth history of a tumor. Exponential growth, the simplest possible growth, is cellular division with a constant dividing time. One cell divides into two and then four, etc., with each doubling taking the same time. This growth is easily recognizable when graphed. It is a straight line on a semi-log scale (logarithmic on the vertical scale and linear on the horizontal scale).

Exponential growth cannot continue indefinitely since it is boundless. Beyond a size where the tumor is a few percent of the host size, the host cannot fully sustain the tumor. At that point exponential growth gradually slows. Growth that is exponential at small time and limited to an asymptotic level at large time is called Gompertzian growth. . According to the 1991 American Cancer Society Textbook of Clinical Oncology , Gompertzian growth accurately describe the growth of breast cancer. When cancer is found in a patient, the tumor lies high on the growth phase of the Gompertz curve and is thus relatively slowly growing. Debulking the tumor by surgical removal and radiation puts any residual tumor in the smaller thus faster growing section of the Gompertz curve and makes it more sensitive to chemotherapy. Due to limitations of human experimentation, there is little hard data. Publications that use Gompertzian kinetics directly or indirectly. There is much well documented evidence to support temporary dormancy in the natural history of breast as well as other cancers. A 4.5 cm. tumor with a constant doubling time of 7200 days leads to the impossible result that the tumor started growing 655 years earlier. The tumor must have grown faster initially and then slowed and finally faster again. That is impossible to explain by Gompertzian growth.

Because of the variability in cancer growth doubling time is of limited value to a treating onclogist. There are, however, aspects of this subject which may be of interest to attorneys. One issue facing the attorney trying to

establish if a delayed diagnosis made any difference in outcome to a patient is whether the tumor grew appreciably between the time it could have been detected and when it was actually detected. If growth is continuous and deterministic as in the Gompertzian model, then every day of delay produces a measurably worse prognosis. If growth is discontinuous and erratic, then some periods of time delay in diagnosis produce no worsening of prognosis while other periods of time delay will produce significant worsening of prognosis. To the attorneys representing either the plaintiff or the accused in a case of delayed diagnosis of breast cancer, it often cannot be established with absolute certainty whether survivability was compromised due to delay. However the probability and the likely extent of damage to survivability can be calculated. For example if after applying the prognostic characteristics cited earlier, one finds that the long term prognosis of the patient as diagnosed is 28% chance of long term survival. One can possibly state with some degree of certainty that if the patient were diagnosed 10 months earlier, the chance of survival would have been 41% to 65%.
Tumors
All organs in the body are made of cells. Individual cells are so small, they can be seen only through a microscope. Normally, cells divide in an orderly fashion to replace cells that have aged and died. Controls within each cell tell it to stop dividing if no new cells are needed. Occasionally, damage to DNA during cell duplication may cause the controls to malfunction. Cells begin to divide uncontrollably, forming lumps or tumors. The word "tumor" comes from a Latin word that means "swelling." A tumor could be composed of cells that divide excessively, but that do not invade or damage other parts of the body. A good example is a fibroid in the uterus, or a fibroadenoma in the breast. Both of these are called benign, that is, non-cancerous tumors. Malignant tumors are composed of aggressively dividing cells that destroy surrounding

tissues or travel to other parts of the body. In general conversation, the word "tumor" is often used to refer to a malignant condition, or cancer.

Growth Rate
Growth rate is the speed at which a lump or tumor grows. Different types of breast cancer grow at different rates. The time it takes for a tumor to become twice as large is called doubling time. The average doubling time for most breast cancer tumors is in the range of 50 to 200 days. The change of the first normal cell into a malignant cell happens years before any evidence of cancer can be detected by any tests that we have today. It may take three to five years for a cluster of cancerous cells to become large enough to be seen on a mammogram. In other words, by the time your cancer has been detected, it has been there for several years. That is why there is no harm in taking a few more weeks to decide on the best treatment possible.

## Types Of Breast Cancer

Breast cancer types are named according to the part of the breast in which they develop. The most common forms of breast cancer come from cells that line the milk ducts (ductal cancer) or the milk-producing lobules (lobular cancer). In the early stages, cancer cells divide locally, and do not cross the wall of the duct or lobule. This type of cancer is called in situ (meaning "in place"). Once the cancer cells cross the lining of the duct or lobule, they are called infiltrating, or invasive. Do not be unduly alarmed if you are told your cancer is "invasive." Most cancers are, so your invasive cancer is the "normal" cancer. Today about one in five cases of diagnosed breast cancers fall into the non-invasive, or in situ categoryeither ductal carcinoma in situ (DCIS), or lobular carcinoma in situ (LCIS).

DCIS cancers are highly curable. Some physicians don't even refer to them as cancer, but rather as "precancerous lesions," since DCIS may never progress to be an invasive cancer. The treatment of DCIS may not follow the same plan as for invasive cancers, so we have dedicated a separate chapter to this non-invasive form of the disease. You still need to read the chapters on staging, surgery and radiation to understand the principles involved. LCIS is a non-invasive growth that is not considered cancerous, but women who are diagnosed with LCIS have about a 1% per year risk of developing invasive breast cancer. That means that twenty years after diagnosis, the risk is about 18%. What is important to know is that the invasive cancer can occur in either breast, and not necessarily where the LCIS was originally found. In other words, LCIS is not a precursor, but a marker. Infiltrating or invasive cancers, where malignant cells cross the lining of the duct or lobule, are more advanced than in situ cancers. They invade, or infiltrate, adjacent tissues. The most common type of breast cancer is the infiltrating ductal carcinoma. More than half of all cases are of this type. Other types of breast cancer are less common. One example is Paget's Disease, a cancerous growth that first appears as scaling on the nipple, and may be confused for a simple rash. Another is inflammatory cancer, a rare form of cancer that grows quickly, causing redness and swelling of the breast. This is really the only form of breast cancer in which the treatment decision needs to be made as soon as possible.