Hormones and Human Breast Cancer: An Account of 15 Years Study

By John Hayward

Recent Results in Cancer Research: Hormones and Human Breast Cancer provides information pertinent to the fundamental aspects of breast cancer and hormones. This book discusses the endocrine factors involved in breast cancer. Organized into two parts encompassing 11 chapters, this book begins with an overview of the process of castration as an effective therapeutic measure in many pre-menopausal patients with advanced breast cancer. This text then discusses the response rate following ablation wherein only 60 percent of patients subjected to hormone therapy as a first treatment for recurrence will survive to ablation. Other chapters consider the microscopical features of a tumor. This book discusses as well the prescription of corticosteroids as treatment, which originates from the mechanism of response that followed adrenalectomy or hypophysectomy. The final chapter deals with the use of radio-immunoassay methods in treating breast cancer. This book is a valuable resource for biochemists, scientists, and physicians.

• Language: English
• Publisher: Elsevier Science
• Release date: Oct 22, 2013
• ISBN: 9781483194172

Book preview

HAYWARD

Chapter 1

Historical Developments

Publisher Summary

This chapter provides an overview of the endocrine factors involved in breast cancer. A historical review of these factors gives little cause for complacency. The behavior of tumors in animals may be quite unlike that of similar tumors in humans. The hormones responsible for breast growth and development may be different. Leo Loeb demonstrated that this incidence decreased in mice of a strain with a natural high incidence of breast cancer in nonbreeders, when they were oophorectomized before 3 months of age. Schinzinger suggested that there might be a relationship between the ovaries and human breast cancer. Removal of the ovaries in patients with breast cancer might cause the breast to atrophy and result in the carcinoma becoming encapsulated in the contracting gland.

An historical review of the endocrine factors involved in breast cancer gives little cause for complacency. After seventy years there is little knowledge of the basic principles involved and treatment by endocrine means is therefore empirical. The physician, in selecting the appropriate therapy for his patient, is still groping in the dark.

Yet an awareness of the advances that have been made over the years can be important, not only to the research worker so that he may gain an understanding of the background of the problem he is investigating, but also to the physician. It is the physician’s responsibility to assess the suitability both of his patient for the treatment and of the treatment for his patient; he has to decide on the type of therapy, how often it should be applied and for how long; and eventually he has to appraise its succes or failure. And at all stages of this involvement he may be influenced by his knowledge of the progress of research and by the extent to which each advance has moulded his approach to the problem.

Animal Studies

It is not the purpose of this book to describe the great volume of work that has been carried out on hormones and breast tumours in animals. Indeed, the behaviour of tumours in animals may be quite unlike that of similar tumours in man. The hormones responsible for breast growth and development may be different and in fact few of the advances in the treatment of the human disease have resulted from animal studies. Nevertheless, the patterns of investigation have often run along similar lines and it is worthwhile considering the major developments that have occurred in the course of animal work—principally in mice.

As early as 1919, Leo Loeb, a worker of prodigious output, demonstrated that mice of a strain with a natural high incidence of breast cancer in non-breeders, had this incidence decreased when they were oophorectomised before three months of age. Subsequently, Murray (1928) showed the converse to be true; mammary tumours could be produced in castrated male mice when an ovary was grafted sub-cutaneously.

By 1932, both natural and synthetic steroids were becoming available and Lacassagne published his classic paper on the development of breast cancer in male mice injected with folliculin benzoate (now known as oestrone benzoate) in oil. In 1935 Alexander Haddow, in a letter to Nature, described the retarding action of certain polycyclic hydrocarbons on the growth of the Jensen rat sarcoma. Many of these hydrocarbons were known carcinogens and it was noted that the greater their carcinogenic activity, the greater was their power to inhibit growth. Some of the carcinogens were also oestrogenic and hence attention was focussed on the synthetic oestrogens which themselves behave as carcinogens under certain conditions in animals. The results were encouraging and eventually a clinical trial was carried out on the use of synthetic oestrogens in the treatment of human cancer.

Plate 1 Prof. Dr. Albert Schinzinger. (Portrait supplied by Dr. Ulrich Roesen, St. Josefkrankenhaus, Freiburg)

In 1946 Shimkin and Wyman further investigated the factors affecting the induction of breast cancer by oestrogens. They showed that the dose of oestrogens was more important than the type of compound used. Male mice were implanted with oestrogen pellets and it was calculated that the dose required to produce breast tumours need not be greater than that secreted by the untreated female.

Following Loeb’s (1919) finding that oophorectomy could be protective against breast carcinoma in mice, Korteweg and Thomas (1939) showed that hypophysectomy decreased the incidence of tumours in susceptible strains. More recently, Shimkin and Wyman (1945) have demonstrated that bilateral adrenalectomy with oophorectomy also decreases murine incidence of breast cancer. In 1949, Foulds reported on a remarkable breast tumour which had a high spontaneous incidence in mice and was hormone responsive. If mice with this tumour became pregnant, the tumours in two-thirds of them grew during the pregnancy and regressed following parturition. In the other one-third of the animals, the tumour appeared to be unresponsive to hormones. It was also noted that the prescription of oestrogens did not affected the growth during the intermission phases.

Plate 2 Sir George Beatson. (Photograph supplied by Prof. A. P. H. Forrest and reproduced by courtesy of Dr. P. F. Peacock and Dr. J. Paul, Beatson Memorial Hospital, Glasgow)

In 1963, Huggins described the production of mammary carcinomas in Sprague-Dawley Rats following one feed of 9-10-dimethyl-l-2-benzanthracene. This extraordinary tumour can be completely extinguished by oophorectomy with adrenalectomy and stimulated to grow again by the administration of oestrogens. The Huggins tumour has proved to be one of the most useful animal systems for investigation.

Plate 3 Dr. Charles Huggins

Human Studies

Schinzinger, a German physician, is credited with the first suggestion that there might be a relationship between the ovaries and human breast cancer. This suggestion was all the more extraordinary because at that time, the concept of hormones as chemical messengers was not formulated. In 1889, he suggested to the Eighteenth Congress of the German Surgical Association that removal of the ovaries in patients with breast cancer might cause the breast to atrophy, and result in the carcinoma becoming encapsulated in the contracting gland. So far as is known this was not put into practice and it remained for George Beatson, a Surgeon at the Glasgow Cancer Hospital, to report on the first definitive removal of the ovaries as treatment for breast cancer. In 1896, Beatson described to the Edinburgh Medico-Chirurgical Society, three patients with advanced breast cancer on two of whom he had performed bilateral salpingo-oophorectomy. Both patients had also received thyroid extract by mouth in the belief that this might act as a lymphatic stimulant. The patients were premenopausal and had tumours which had taken many years to grow and become disseminated. In each case, he noted a response and the tumour deposits decreased in size or disappeared.

Plate 4 Prof. Sir Hedley Atkins, K. B. E.

In 1895, when these operations were performed, the theory of the bacterial basis of disease was widely accepted. Cancer was thought to be due to so called cancer bodies—parasitic, intra-cellular organisms which were believed to cause the cellular activity and proliferation characteristic of malignant growth. Beatson himself did not subscribe to this theory and preferred the unorthodox view that these intracellular bodies were simply products of cell breakdown and degeneration:

I have felt for sometime, that the parasitic theory of cancer is an unsatisfactory one in many ways and that in directing all our energies to working it out we are losing time and searching for what will never be found, simply because it does not exist.

At this time, the function of the breast and particularly that of lactation was believed to be under nervous control. Earlier in his life, whilst working for his M. D. Thesis, Beatson had studied lactation in the sheep and had formed the opinion that one organ might influence the secretion of another organ without direct nervous control. He described his idea in what must be one of the first direct references to the action of hormones:

I am satisfied that in the ovary of the female and the testicle of the male, we have organs that send out influences more subtle and more mysterious that those emanating from the nervous system.

With remarkable foresight he went on to suggest that the ovaries might be the seat of the cause of carcinoma of the breast.

These were highly original and contentious thoughts and, although ovariotomy was frequently practised, its use under these circumstances seemed so outrageous that it led Beatson to anticipate criticism and even condemnation. He ended his paper by pleading that he had been activated solely by the motives that guide all of us in the exercise of our profession; primarily, the interests of those who place themselves under our care and secondarily, the progress and advancement of the healing art.

There was no condemnation, nor even a word of comment. This singular description of how the growth of a malignant tumour could be influenced by treatment other than direct surgery was ignored. Beatson’s paper was not accompanied by a leading article or annotation, nor was there any correspondence on the subject in ensuing copies of the Lancet.

And yet the point that oophorectomy could favourably affect the progress of advanced breast cancer had obviously been taken—probably because any therapy, however extraordinary, was worth trying for a condition that was otherwise untreatable. Within one year, further cases were being described to the East Anglian Branch of the British Medical Association and within two years, another report had appeared in the literature (Herman, 1898). By 1900, Stanley Boyd of the Charing Cross Hospital, was able to collect from various surgeons fifty-four cases of oophorectomy in advanced breast cancer. He reported that about one third responded (a figure that has not changed over the years) and stated that he was looking for methods to predict which patients would respond. We are still looking.

During the ensuing few years several further series appeared in the literature. The operation appears to have been confined to the treatment of advanced cases and its use as prophylaxis at mastectomy did not come until much later. Meanwhile, X-rays had been discovered and were developed, and it was not long before therapeutic doses of radiation were applied to the ovaries as a method of castration. By 1905, De Courmelles was irradiating the ovaries of patients with advanced breast cancer. In 1922, he described to the French Academie des Sciences, the advantages of a combined approach in the treatment of the locally advanced disease. He advised that both the tumour and the ovaries should be irradiated and mentioned two patients who had survived fifteen years following this treatment. In 1926, he reported that the response to ovarian irradiation was similar to that obtained by surgical ablation. The merits of the two methods of eliminating ovarian function are still being compared and debated.

In the early 1930’s, natural and synthetic steroids became available and were investigated as treatment for the advanced disease. In 1939, Ulrich described two patients with breast cancer who had remissions following treatment with testosterone, and further reports on larger series were soon in the literature. There was no agreement on the value of androgens as therapy and indeed, one of the earliest reports might have persuaded surgeons not to pursue their use. Farrow and Woodard (1942) described the changes in serum calcium levels than can follow the injection of testosterone propionate in patients with metastatic deposits in bones. They believed that the hormone stimulated the metastatic growth causing the ensuing hypercalcaemia, and they suggested that this effect contra-indicated the use of androgens in treatment. Further studies did not endorse this suggestion, and androgens were soon accepted as treatment for the advanced disease.

In 1944, Haddow and his colleagues, reported on a series of seventy three patients with primary cancers at many sites who had been treated with synthetic oestrogens. Triphenylchlorethylene, tryphenylmethylethylene and stilboestrol were used, and cancer of both the breast and prostate responded to the therapy. Stilboestrol proved to be the most active compound and was soon accepted as the drug of choice in the treatment of advanced breast cancer in post menopausal