by Roberto Kusminsky, MD
The structured surgical treatment of breast cancer began in 1882 when William Halsted, a professor of surgery and one of the founding members of the Johns Hopkins Hospital, developed an operation known as a radical mastectomy, in which the breast and the underlying muscles plus the lymph nodes in the armpit were removed.
Halstead, an influential and well-known surgeon, theorized that breast cancer was a disease confined to just one area which spread, he thought, in a predictable manner along the lymphatic channels draining the tumor. So he believed that removing the cancer with a wide margin of tissue would give patients the opportunity to be cured.
In 1896 radiation treatments were initiated by Emil Herman Grubbe, a physician from Chicago, who assembled the first ever X-ray machine and treated a woman with breast cancer. That was just a few months after X-rays were discovered by Wilhelm Roentgen, a professor of physics in Worzburg, Bavaria.
Grubbe ended up having approximately 90 operations for multiple cancers because of his exposure to X-rays. Eventually he lost his forearm and hand, and most of his nose, upper jaw and lip to radiation induced tumors.
The original radiotherapy initiated by Grubbe improved significantly with two simultaneous advances.
One took place in the late 1930s, when scientists Glenn Seaborg and John Livingood at the University of California discovered the radioactive form of cobalt, a metal used for centuries to color porcelain, glass, tile and pottery. This radioactive material was used to treat a cancer patient for the first time in 1951, in Ontario, Canada.
The second development was the recognition that an “atom smasher” could be used for cancer therapy. This machine had been conceived in 1924 by Gustaf Ising, a Swedish physicist, and independently in 1928 by Leo Szilard, a Hungarian-born physicist who was not aware of Ising’s work. Szilard was also the one who conceived the nuclear reactor, the electron microscope and participated in the development of the Manhattan project, which built the atomic bomb.
The “smasher” was a linear accelerator, so called because subatomic-sized particles could be accelerated to the speed of light, and in this manner they were able to produce high-energy x-ray beams that reached deeper tissues in a more focused way, sparing many of the normal cells while killing the cancerous ones.
A linear accelerator was first used at Stanford University in 1956 to treat a 2-year-old boy who had an eye tumor: the treatment did away with the cancer and preserved the child’s vision, an accomplishment that would not have been possible with the older type of radiation treatment.
These improvements were happening at a time when the most significant finding of the 20th century was made: the discovery in 1952 of the structure of DNA by Watson, an American, and Crick, from England. DNA is the blueprint in our cells that determines who and how we are. This breakthrough opened the door to understanding the genetics of cancer and gave scientists the initial tools to eventually defeat it.
In those days, chemotherapy was also joining the arsenal of weapons to treat cancer, with the first drugs developed between 1940 and 1952. The first such drug was nitrogen mustard, a discovery that arose from clever observations from scientists involved in the study of a World War II event.
In 1943, the USS John Harvey was sunk by German aircraft at the port of Bari, in southern Italy. The ship was carrying a secret cargo of 2,000 nitrogen mustard bombs, a toxic substance that had been used for chemical warfare during World War I. The sinking caused the unintentional release of the deadly material. More than 1,000 people were exposed and many died. Autopsies showed that lymphoid cells had been destroyed by the mustard, and so the drug was tested in the treatment of lymphomas, with success.
Concepts of how cancer spread, its causation and prevention were also evolving. By the end of the 1950s it became clear that radical surgery was associated with some failures, suggesting that breast cancer might not be associated with the mechanisms of spread envisioned by Halstead.
Prevention thinking in those days was still immature. In 1960 smoking was culturally accepted, so the first suggestions in 1962 that smoking caused cancer were seen with some degree of skepticism. In 1960 medical oncology did not yet exist as a specialty, and it wasn’t until 1973 that it became established as one, with chemotherapy as the tools of the trade.
Advances began to add up. In 1965, a significant development in the treatment of cancer was made when a combination of several drugs demonstrated a clear improvement in outcomes when compared with the use of single agents. Between 1967 and 1970, studies demonstrated that patients with Hodgkin’s disease (a type of cancer from lymph tissue that was until then difficult to treat), became free of the disease in 80 percent of the cases treated with drug combinations. Follow up studies confirmed that 60 percent of those patients had no signs of the illness even after 40 years of follow-up. So this approach became the new standard of care, replacing older methods of therapy.
There was progress in the detection methods of cancer as well. In 1967, Sir Godfrey Hounsfield, an electrical engineer, was taking a walk on a field in his native England, and saw an empty box. He imagined that he could see what was inside of it by taking X-ray images of the box in successive slices and then reconstructing them with the help of a computer. He proceeded to build the prototype of a CT scanner, which was used on a human for the first time in 1971.
This was followed by construction of a whole body scanner in 1975. Hounsfield went on to win the Nobel Prize for Medicine in 1979. Concurrently, the Breast Cancer Detection Demonstration Project of 1973 revealed that 85 to 90 percent of asymptomatic breast cancers were discovered by mammograms given to 283,000 women, with an important reduction in mortality as the result.
Progress continued. Between 1971 and 1976 surgical procedures preserving the breast showed excellent results, and in 1976 the addition of chemotherapy after surgery (known as adjuvant chemotherapy) showed a major improvement in survival.
By the 1980s, genetics was contributing to the understanding of cancer, with the discovery of defects in the so-called onco-genes and tumor suppressor genes. Think of it as the gas pedal in your car: Pressing the pedal is similar to the function of an onco-gene, which accelerates the growth of a cancer cell. The tumor suppressor gene is the brake, which in some cancers does not function and so it releases the cancer cell from the mechanisms that might keep it in check otherwise.
In 1975, biochemistry experts Cesar Milstein and Georges Kohler, working in their laboratory at the University of Cambridge, developed a special type of antibody for which they won the Nobel Prize of Medicine in 1984. An antibody is a substance produced by the immune system that attacks anything entering our bodies that is recognized as potentially harmful.
These types of antibodies, called monoclonal antibodies, became the platform used for the creation of drugs with specific properties which were then and are now used to attack and kill cancer by targeting a particular characteristic of its cells. This is, therefore, known as “targeted therapy.” The first such drug for breast cancer, called Herceptin, was used in 1991 with excellent results, and it gained FDA approval in 1998.
Progress picked up speed
In 1994, alterations in two important genes responsible for inherited breast cancer were discovered, the BRCA 1 and 2 genes. Everybody has the BRCA genes, and only a small percentage of people have the changes in them that induce breast cancer. Drugs were next developed, with specific molecular targets which had been recognized in cancer cells thanks to the advances in genetics.
In 2001, a drug (a monoclonal antibody named Gleevec) was developed that changed radically the prognosis of patients with Chronic Myelogenous Leukemia and increased their survival significantly, from 20 percent to 85 percent at 10 years. That same drug was found to be effective in the treatment of patients with other, less common cancers. There are now more than 15 similar drugs approved by the FDA and approximately 500 others in clinical trials testing them.
At this point, the pace of discovery and innovation quickened again, with successful achievements occurring simultaneously in several fronts.
In 2011, a drug was developed that for the first time resulted in prolonging survival of patients with metastatic melanoma (cancer that has spread).
Between 2010 and 2013 another breakthrough took place, in which immunotherapy resulted in the cure of children with leukemias that had not responded to traditional chemotherapy treatments. This fascinating result was accomplished by a revolutionary feat of bioengineering. Special cells of the immune system were removed from a patient, and they were biologically re-engineered to attack cancer cells. These modified immune cells were then re-injected into the same patient, with the results described above. This kind of success had never been obtained this way before, and many experts believe that this could eventually lead to abandon chemotherapy altogether and use instead immunotherapy to treat cancer.
In 2014, another far-reaching breakthrough was reported. Patients with metastatic breast cancer were treated with a combination of new target-seeking drugs rather than using only one agent. This resulted in an average improvement in survival of 16.5 months, something never seen before. This unprecedented outcome created a new standard of care, and clearly suggested that control of metastatic disease of the breast is no longer an impossibility.
Other advances currently in use are the new antibody-drug conjugates, in which a chemotherapeutic drug is joined to a specific antibody. This compound then attaches itself to a cancer cell and kills it, without affecting normal cells. In 2012, studies using this approach in patients with metastatic breast cancer also resulted in an improved survival.
In 2015, the government is funding nanotechnology research at $1.5 billion. Nanotechnology is the manipulation of matter at the atomic or molecular level. In this dimension, matter responds differently to physical laws. For instance, at molecular sizes, a special compound loaded with a treatment drug can be sent into the body of a patient and expect that such combination will not be recognized as an invader and consequently be attacked by the immune system. Other important applications are quite possible, such as creating and using nanorobots to deliver drugs, repair cells, make cancer cells heat up and die when stimulated by infrared light from outside the body, produce tiny sensors that will attach, recognize and destroy cancer cells when they first appear, and much more.
So, what has been accomplished so far?
Until 1990, the number of cases and the mortality from breast cancer had been increasing. Since then, the mortality has decreased, so in the last 24 years we have seen a drop in the death rate from breast cancer of 34 percent. And this decline in mortality sped up since 2007.
In 1975 the survival rate from breast cancer at five years was 75 percent. By 1990 it had increased to 85 percent. And in 2006 it was 91 percent.
And as of 2010, we were detecting a larger percentage of localized breast cancer, a percentage that would improve if patients heed their physician’s advice. And the survival rate at five years for localized breast cancer is an incredible 98.5 percent.
We have learned and progressed more in the last 10 years than we have in the previous 100, and the progress has been incremental, but real.
John Erichsen, a famous British surgeon, wrote “That we have reached the final limits in this department of our profession there can be little question.”
His incorrect and prejudiced prophesy was written in 1873. Now, a complex, diabolical ailment is turning into a better defined problem with specific solutions. These solutions derive from molecular deciphering, biology and tissue engineering, molecular therapies, immunotherapy, combination treatments, new drugs, and the promise of nanotechnology. So, we have better and earlier detection, better chances of prevention, better treatments. Therefore, the question should not be if we can cure breast cancer. The question should be: When?
Dr. Roberto E. Kusminsky is professor and chairman of the Department of Surgery at West Virginia University/Charleston Division and medical director of the Breast Center at CAMC.