Bethesda, Maryland, United States (Winter 2018)
“As to diseases, make a habit of two things — to help, or at least, to do no harm.” ― Hippocrates (circa 400 BCE)
|Imhotep: physician, architect and
adviser to Pharaoh Djoser, 26th Century BCE
As a scientist, I see breast cancer as a biological process that starts with a single cell that becomes unregulated, then multiplies relentlessly until it kills the host, unless fully treated. That is not this story. Rather, this is a story of the profession of medicine and of practices taught from generation to generation by revered professors and faithfully followed until evidence intruded to break the cycle of certainty.
Breast cancer is not new. In 1842 Edwin Smith, a rich man with a passion for Egypt, bought a four-meter papyrus scroll written about 1600 years BCE. It turned out to be an unfinished copy of writings attributed to Imhotep, a physician and advisor to a pharaoh who lived a thousand years earlier. What was written, however, was fascinating: a clinical listing of forty-eight cases and advice. Of special interest here is Case 46, in which Imhotep describes a woman with bulging lumps in her breast that “feel like an unripened fruit” and states bluntly that “there is no therapy for this disease” and “not even a magic potion will work.”
Herodotus, the Greek historian circa 440 BCE, next mentions breast cancer in his story of Atossa, the daughter of a Persian emperor, who lived 100 years earlier. He describes the princess as having a breast lump steadily increasing in size. On the advice of her Greek slave, she had her breast cut off. She evidently survived the ordeal because it happened “in the middle of her reign.” Moreover, she was so impressed by the cleverness of the Greeks that she asked her father, Cyrus the Great, to invade Greece – we know how that turned out for both sides, and for European history.
Of course, physicians must have seen breast cancer throughout the ages, although there was nothing they could offer their patients. Finally, in the 1750s French surgeons began advising their patients to have the cancer cut out. Consider what this radical approach meant in an era without anesthetics, without antibiotics, without any understanding of germ theory at all. Few women would have survived. In 1770 John Hunter, the ever-practical Scottish surgeon, examined available data with his precise clinical mind. He concluded that only if the lump were small would it ever work. For the rest, “abstract sympathy” was his best advice, but this desperate practice continued.
Medicine as a “science” began to gain traction only about 150 years ago. For surgery, anesthesia (1840s) and the germ theory (1880s) were critical developments. Joseph Lister, a British surgeon in this 1880s, is credited as the first to apply germ theory to surgery. He noted that infections in the laboratory could be prevented by filters, heat, and chemicals. Filtration and heat being impractical in patients, he settled on carbolic acid, a phenol derivative of coal tar. Carbolic acid had been developed to prevent sewage from smelling, so Lister reasoned it must kill germs. It seemed safe enough since cows eating grass nearby appeared to be healthy. In a clinical trial on a single patient, he applied it to a dressing covering an open fracture. It appeared to work – the young boy did not get infected and his injury healed.
With that limited evidence, Lister began promoting its use in operating rooms with the enthusiasm of a preacher. He used it everywhere, even spraying the air around the patient. Even so, he was famous for coming to surgery directly from the autopsy room, his coat covered with blood and fluids from dissected bodies, and he once did a successful mastectomy on his sister-in-law on her own dining-room table – at least, she recovered from the surgery. More usefully, carbolic acid was so irritating to skin that surgeons started wearing gloves to prevent incapacitating rashes.
Surgery being feasible, breast cancer management was transformed. A prominent leader in this was William Halsted, head of surgery at Johns Hopkins Medical School in 1900 and mentor to the leading generation of surgeons in the United States during this era. Halsted specialized in breast cancer, famously recommending ever-wider margins for cutting away tissue. He built his reasoning on work reported in 1895 by a Scottish surgeon, Charles Moore. Moore did a careful study of patients, finding that in failed surgeries, the tumor appeared first at the margins. If this was true, then the answer was to take more tissue. “Avoid mistaken kindness” became the Halsted mantra and ultimately the doctrine of American surgery for almost a hundred years.
Did it work? Halsted only once reviewed his own experience.1 The results were not impressive. Half of his patients died in three years and only three of sixty survived to five years if they had lymph node swelling. His conclusion? Remove more tissue! He and the generations of students that followed espoused “radical mastectomy,” taking all the nodes they could find and even muscle tissue, down to bone if needed. Many women were cured but with a huge burden of post-operative complications, including lymphedema and disfiguring mutilation.
Not everyone jumped aboard this American surgical frenzy. Geoffrey Keynes, a pillar of British surgery, strongly disagreed, arguing instead for simply mastectomy or lump removal when the tumor was small. Thanks to his influence, British surgeons typically used limited surgery throughout much of the twentieth century, with good results. In the US, however, surgeons dismissed simple mastectomy as “lumpectomy” and considered it malpractice. Oddly, there were no serious attempts to compare the outcome for many decades, and the trans-Atlantic controversy over lumpectomy versus radical mastectomy persisted, sometimes with vitriol. Halsted’s view of “take more tissue” prevailed in the US, and American patients opting for lumpectomy had to go to Europe for surgery.
After seventy years of debate, a large multicenter US/Canadian study headed by Bernard Fisher, an oncologist at the University of Pittsburgh, finally tested the two approaches in a randomized clinical trial. There were terrible difficulties getting patients to enroll. Righteous surgeons across the nation excoriated the study and urged their patients to avoid enrolling, and the trial took far longer than expected. However, when the result came, it proved a shock to the Americans: radical surgery was no better than simple approaches.2 Generations of American surgeons were wrong. Certainly, go beyond the margins of the tumor. Take a sample of lymph nodes to assess spread and guide further therapy. But massive blind resections of tissue were mutilating and destructive, not more curative.
We are now rapidly moving into the genetic era permitting prediction of breast cancer risk in some women. Depending on how a woman with a genetic risk feels, she may elect prophylactic surgical mastectomy, itself a controversial issue that requires genetic counseling to balance the benefits and risks of surgery. The major breakthrough in genetic insight came with the work of Mary Clair King, a geneticist in San Francisco who reported two major genes conferring breast cancer risk: breast cancer gene type 1 (2- to 3- fold risk incidence increase in carriers) and a rarer type 2 (5-fold increase). While large relative increases, the overall absolute risks in carrier remains small. In today’s DNA world, geneticists find new gene associations regularly, although each has a progressively smaller impact on risk, and the most recent assessment is that genetic variation may affect about 25% of the risk of breast cancer.
So where are we now? From “there is no therapy” in Imhotep’s observations of 4500 years ago to today, we have come a long way. Over 80% of women diagnosed with breast cancer can expect to be “cured” and live a normal lifespan without complications. The average woman diagnosed with breast cancer at age sixty can expect to live until eighty-two, which is 84% of the survival time she might expect if she had never been diagnosed with breast cancer.3 About half of the longer survival is due to earlier detection by education, self-assessment, and mammograms, and half to better management of cancers with surgery, hormones, and chemotherapy. And there is every reason to hope each of these approaches will get even better.
It is an amazing advance and a credit to medicine. However, there is a cost to all this, about a half million US dollars per case. With 40,000 new cases each year in the US, that comes to twenty billion dollars annually just in the US. So it is not cheap – and with personalized medicine, new advances will probably become more expensive in the future.
Breast cancer will probably always be with us. Cancer is a natural process, a byproduct of being alive. We may detect and remove it. We may manage it when it escapes our attempts at control. But it will occur. In fact, because of our changing lifestyles that forgo or delay pregnancies, the incidence of breast cancer will probably increase in the future.
I leave you with a few thoughts from this story. Many of the events described are not from ancient history but rather took place in our lifetime and within our own personal experience. Professionals are trained to repeat what they were taught and do it well. However, the absolute certainty of doctors is provably wrong – even today. Experience and logic may be starting points for patient care, but solid evidence of efficacy should be required for all invasive interventions. And consider what gain means. There is a cost of our ignorance, not only for society but also for the patients who suffer because of it.
To quote Bernie Fisher: “In God we trust. All others must have data.”
- Halsted, William S. (1894–1895). “The results of operations for the cure of cancer of the breast performed at the Johns Hopkins Hospital from June, 1899, to January, 1894”. The Johns Hopkins Hospital Reports. 4: 297.
- Bernard Fisher, Stewart Anderson, John Bryant, Richard G. Margolese, Melvin Deutsch, Edwin R. Fisher, Jong-Hyeon Jeong and Norman Wolmark, Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. The New England Journal of Medicine. 347:1233–1241, 2002.
- Peter D. Baade, Daniel R. Youlden, Theresea M-L. Andersson, Philippa H. Youl , Euan T. Walpole, Michael G. Kimlin, Joanne F. Aitken, Robert J. Biggar. Temporal changes in loss of life expectancy due to cancer in Australia: a flexible parametric approach. Cancer Causes Control. 27:955-64, 2016.
ROBERT J. BIGGAR, MD, retired in 2014 after forty years of cancer research, most with the National Cancer Institute, Bethesda, Maryland. His most recent position was as Professor of Research Development at Queensland University of Technology in Brisbane, Australia. He now volunteers at NCI. His research interests focus on cancer etiology and public health, including studies on breast cancer etiology and survival. He has written 344 articles and three books on cancer and viruses. He has also written five novels and short stories.