Journalist(s):

Janet Fricker

Introduction

Breast-conserving surgery is one of the most important cancer treatments. It is the standard of care for early stage breast cancer as it minimises removal of healthy breast tissue and preserves as much of the breast as possible. Radiation therapy is usually given after surgery to kill cancer cells that may still be present in the breast, and drug therapy may also be offered.

The crucial aspect is that it has become the alternative to mastectomy ‒ surgical removal of the entire breast, which historically also extended to removing the pectoral (chest wall) muscles under the breast, and lymph nodes in the axilla (underarm) and the neck.

Breast-conserving therapy has similar rates of survival to mastectomy while greatly improving quality of life by reducing complications such as long-term pain, loss of arm strength and lymphoedema ‒ swelling of the arm and hand. It also has much better aesthetic results, which can be immensely important to a woman's identity, sexuality and self-confidence.

It has also contributed to breast cancers being diagnosed at an early stage by reducing fear of surgery after diagnosis, and so is an incentive to get diagnosed as early as possible. In turn this has improved survival.

The story of breast-conserving therapy stems from theory that breast cancers spread locally rather than systemically and could be cured with a sufficiently radical excision, namely mastectomy. But after many years this was shown not to be the case.

Radical mastectomy was developed in the late 19th century by the US surgeon William Stewart Halsted and was applied for almost 100 years until epidemiological studies found a lack of curative impact. Biological and pathology studies showed breast cancer cells spread systemically, and randomised trials demonstrated that, for early stage cancers, adequate control of the disease could be achieved with less surgery, with the additional benefit of better functional and aesthetic outcomes.

It was Europeans who led the challenge to Halsted's mastectomy driven by insights into the limited cure rate it achieved and recognition of the impact such radical surgery has on women. In the 1920s, Geoffrey Keynes, a British surgeon wanted to avoid unnecessary mutilation after his experience as a field surgeon in the first world war. He was the first to propose using radiotherapy to support less surgery, publishing results of his first series in 1931.

In the following decades it was other British surgeons – among them David Patey and John Madden – who introduced modifications to radical mastectomy that involved sparing the major and minor chest (pectoralis) muscles. While this was widely adopted in Europe, Halsted's radical mastectomy held sway in the US.

Finally, in the late 1960s, the idea that all breast tissue had to be removed was challenged by Umberto Veronesi in Italy with the quadrantectomy procedure, in parallel with Bernard Fisher in the US who developed lumpectomy (see below for descriptions of the procedures). Their pathology and biology studies, followed by randomised controlled trials, demonstrated conclusively that restricting the excision to the area immediately around the tumour, followed by radiotherapy, gave survival as good as radical mastectomy.

As a result of these trials, breast-conserving surgery and radiotherapy have become the standard management of stage I/II breast cancer, with mastectomy reserved for patients with more advanced disease.

Veronesi – whose approach to treatment was 'minimum effective' rather than 'maximum tolerable' – would later reduce further the extent of surgery. Working with nuclear medicine specialist Giovanni Paganelli his team introduced the sentinel lymph node biopsy (SNLB), which can prevent the widespread excision of axillary lymph nodes, and radioguided occult lesion localisation (ROLL), to guide surgeons more accurately towards lesions that are visible on imaging but too small to be felt by hand.

The development of breast-conserving surgery went hand in hand with the evolution of understanding about the nature and natural course of breast cancer, and of other cancers. Understanding how cancers spread and become metastatic has had profound implications for how to treat them effectively.

Early history of breast cancer surgery: from ancient Egypt to the Roman empire

Breast cancer surgery has been performed for thousands of years and there are varying accounts of who did the first procedures. Compared with other parts of the body the breast is more easily accessible, which is why breast removal was one of the earliest forms of cancer surgery.

The Edwin Smith Papyrus, a medical text from ancient Egypt of about 3,000–2,500 BCE (named after the archaeologist who translated the text in 1862), has what is thought to be the first account of breast cancer. The papyrus, commonly attributed to Imhotep ‒ an Egyptian polymath who, as well as being an engineer and architect, was also a physician ‒ described breast cancers as 'cool bulging' tumours and breast abscesses as 'hot bulging' tumours. The document recommended that doctors should not do surgery and instead manage tumours with cauterisation, a procedure referred to as the 'fire drill'.

Hippocrates, the famous Greek physician born in about 460 BCE on the Aegean island of Kos, who is often seen as the father of medicine, developed the four humours theory of disease: illness was caused by imbalances of blood, phlegm and yellow and black bile. Cancer, he reasoned, was a systemic disease arising from an excess of black bile (melancholia). Hippocrates argued against the practice of breast surgery: "It is better not to excise hidden cancer, for those who are excised quickly perish; while they who are not excised live longer."

Galen,a Greek practising medicine in Rome from 162 CE, supported Hippocrates's theory, arguing that if black bile was not cleansed through the spleen, veins became congested, thereby creating tumours. Menstruation, he reasoned, relieved women of excess black bile ‒ a theory providing an explanation for the increased incidence of breast cancer observed in postmenopausal women. The therapeutic consequences of the black bile theory, wrote Craig Henderson and Michael Baum in Classic Papers in Breast Disease, "was 1,500 years of cupping, leaching, venesection, purgation, and crank diets".

The first mastectomy in 1st century– but a dark age up until 13th–14th centuries

The first description of mastectomy is attributed to Leonidas (1st century CE), a Greek physician from Alexandria, who advocated removal of healthy tissue leaving wide margins of excision and only removing tumours of limited extent. Hot irons were used to cauterise incised tissues, serving the dual purpose of stopping haemorrhage and eradicating disease.

In the Middle Ages, medicine suffered a setback when early Christians believed disease to be punishment from God and favoured faith healing and miracles over surgery.

Most early mastectomies followed the approach of pulling the breast away from the body, followed by removal of the whole breast with a sharp implement. In France, instruments to enable rapid removal of breast tumours were introduced by Henri de Mondeville in the 13th century and Guy de Chauliac in the 14th century. De Chauliac also supported application of caustic pastes to clean wounds after surgical removal of the tumour and treated operable cancers with wide excisions. See James Pilcher's Guy de Chauliac and Henri de Mondeville – a surgical retrospect published in 1895.

Accurate identification of the originators of many breast cancer surgical techniques is impossible, argues Alanna Skuse in Constructions of Cancer in Early Modern England, as most surgical practice was not recorded. Furthermore, the limited medical textbooks of the time provided operating instructions without indicating whether the author had carried out the procedure.

Mike Dixon, a breast cancer surgeon based in Edinburgh, Scotland, said that, throughout history, it has been challenging to identify the provenance of many breast cancer surgical procedures. "The reality is that often many people took similar approaches around the same time. The person who got the credit wasn't always the prime mover but the first one to write it up," he said.

For more details see Breast cancer surgery: an historical narrative. Part I. From prehistoric times to Renaissance, by George Sakorafas and Michael Safioleas, and Historical review of breast cancer surgery, by Damir Grebić and colleagues.

Advances in anatomy: Renaissance surgery in 15th –17th centuries

Anatomical descriptions by Flemish physician Andreas Vesalius in the 16th century, and Italian polymath Leonardo da Vinci provided better understanding of the breast, leading to advances in surgical techniques. Notably, Vesalius used ligatures instead of hot cautery when excising breast tumours and advised wide margins, and Petrus Severinus advocated removal of axillary lymph nodes in addition to the breast, and was one of the first physicians to associate lymph nodes with malignant processes.

Other notable contributions included Spanish surgeon Francisco de Arceo, who dissolved tumours by means of ligature; Parisian surgeon Ambroise Paré, who compressed the base of the breast with lead plates to induce ischemia in an attempt to arrest disease progression; and German surgeon Wilhelm Fabricius von Hilded, who devised an instrument which constricted and fixed the base of the breast so that the knife could amputate the breast quickly to reduce pain.

See again Breast cancer surgery: an historical narrative. Part I.

"One of the most curious aspects of early modern cancer surgery is the fact that not a single text I have examined mentions the change in bodily appearance affected by mastectomy, even obscurely. For those who survived this perilous operation, it seems that surgeons were reluctant to confront the possible costs of their success, or to undo the detachment from their patients which allowed them to carry and construct as progressive, such risky procedures," wrote medical historian Alanna Skuse.

Lymphatic theory and the rise of local treatment approaches: 18th century

In 1757, French surgeon Henri Le Dran observed how involvement of the axillary nodes indicated worse prognosis in breast cancer patients. From this he reasoned that breast cancer spread through the lymphatic system and then into the general circulation.

The lymphatic theory offered hope that breast cancer might be cured if surgery was performed sufficiently early, but raised concerns that if 'cancer lymph' passed beyond adjacent lymph nodes, the entire lymphatic system would become contaminated.

Le Dran's reasoning led to the eventual replacement of the humoral theory of breast cancer, although this did not become widely accepted for another century. From such interpretations the underlying principle of curative surgery became to perform wide en bloc; that is, removing the breast in one piece.

It was Jean-Louis Petit, appointed as the first director-general of the Royal Academy of Surgery in France in 1731, and a contemporary of Le Dran, who first put these theories into practice. In his book Traité des maladies chirurgicals, et des operations qui leur conviennent, published in 1774, 24 years after his death, Petit outlines what -. The procedure involved excising the breast, palpable axillary lymph nodes and underlying pectoral lymph nodes, and even pectoralis major muscle if attached to the tumour.

But lack of anaesthesia, blood transfusions and antiseptics greatly reduced enthusiasm for such extensive surgery.

Recurrence patterns support local treatment approaches: 19th century

In 1867, Charles Hewitt Moore, at Middlesex Hospital, London, revived the theory of local origin of breast cancer. Following limited surgery for breast cancer he observed that recurrences arose near the scar, with a pattern suggesting 'centrifugal' spread from the original site. Moore became convinced that 'piecemeal' mastectomies, where the breast tissue was removed in pieces, spread the 'element in the surgical wound' and was responsible for local recurrence. Moore's observations led to a principle of surgical cure involving removing the whole breast, and skin, stressing that tumours should not be divided. He also recommended removal of axillary nodes and the pectoral muscles if they were involved.

German physician Rudolf Carl Virchow – who published a classic text, Cellular Pathology, in 1858, and is seen as the father of this new science – was the first to describe the cellular nature of cancer. From post-mortem dissections of women who had died from advanced breast cancer, he demonstrated that cancer arose from epithelial cells and then spread along fascial planes and lymphatic channels. From such observations, Virchow argued that tumours spread locally through the lymph nodes as opposed to the blood stream, and that lymph nodes acted as 'filters' that temporarily slowed the spread of cancer. The concept gave rise to the idea that, with adequate surgery, cancer might be cured at an early stage, contradicting Galen's view that cancer was the local manifestation of a systemic disease.

Precursors to radical mastectomy: 19th century

Even before then, Virchow's pathological findings had influenced the surgical practices of a number of prominent surgeons, including Richard von Volkmann and Lothar Heidenhain in Germany and Theodor Billroth in Vienna. The findings persuaded these surgeons to adopt the surgical practices that had been conceived by Charles Hewitt Moore. In 1875, von Volkman advised removing the superficial fibres of the pectoralis major muscle, writing: "I was led to adopt this procedure because of microscopic examinations I repeatedly found, when I had not expected it, that the fascia was already carcinomatous, whereas the muscle was certainly not involved." From this von Volkman introduced a new technique where he removed the entire breast, a liberal piece of skin and pectoral fascia, and performed axillary node dissection in cases when they were enlarged. Heidenhain went further, even suggesting removal of the entire pectoralis muscle if the cancer had infiltrated part of the fascia or muscle.

That Virchow's theories had far-reaching consequences that influenced the practice of breast surgery into the middle of the 20th century can be attributed to a young American surgeon, William Stewart Halsted, who came across them on his 'surgical tour 'of Europe in 1877. Taking his inspiration from Virchow, Halsted believed that breast and other cancers began as small tumours that then enlarged in 'slow, orderly, centrifugal' patterns, leading him to suggest extensive operations performed early enough avoided local recurrence, where cancer returned in the field of the operation. He reasoned use of 'en bloc' dissection would avoid cutting through cancerous tissue and liberating cancer cells.

While observing surgical techniques of von Volkman and Bilroth, Halsted came to the conclusion their high rates of local recurrence and low survival rates following breast cancer procedures were due to inadequate removal of tissue surrounding the cancer. He learned that Bilroth's mastectomy patients had an 82% chance of developing new tumours on their chest walls, while von Volkman, who removed the fascia of the chest muscles along with the breast and axilla, had only 60% of patients suffering a recurrence.

Another key figure was William Sampson Handley, a British surgeon who worked at Middlesex Hospital, London, who supported Virchow's view. Undertaking microscopic studies, Handley showed the main extension of cancer was along the lymphatics, coining the term 'lymphatic permeation', where cancer spreads in a centrifugal pattern, along the plane of deep fascia beneath the skin and along lymphatic vessels. This was another plank in the scientific rationale for Halsted's radical approach.

Halsted's radical mastectomy: late 19th century

Returning to the US, where he was appointed chief of surgery at the Johns Hopkins Hospital, Baltimore, Halsted developed an operation that, while resembling German procedures, went much further. In a procedure he called radical mastectomy, Halsted removed the entire pectoralis major muscle, using the word 'radical' in the original Latin sense meaning 'root'. By 1898 Halsted had extended his procedure to include excision of the supraclavicular lymph nodes and pectoralis minor muscle, including use of skin grafts to cover up the 'mastectomy defect', a technique that he had again learnt in Germany from Karl (or Carl) Thiersch.

It is clear that Halsted's surgical approach can in no way be considered original, and that he took much of his inspiration from European surgeons and scientists. "He synthesised the best points in the techniques which had been suggested by the most advanced surgeons of that period," write Sakorafas and Safioleas, in part II of their historical narrative on breast cancer surgery. Another American surgeon and a contemporary of Halsted, Willy Meyer, was also a proponent of radical mastectomy.

In his first paper, Halsted describes 50 patients operated on by radical mastectomy, claiming they only experienced 6% local recurrence, comparing favourably with the results of surgeons in Europe performing the 'von Volkman mastectomy', where recurrence rates ranged from 50% to 80%. But his follow-up was short (a maximum of three years and seven months).

While Halsted's follow-up showed mastectomy achieved good local control at least in the short term, he was unable to draw any conclusions about long-term overall survival from it. "We can state positively that cancer of the breast is a curable disease if operated upon properly and in time," Halsted concluded.

In 1898, Halsted reported to the American Surgical Association the results of 133 breast cancer operations performed at Johns Hopkins over nine years, of which 9% had local recurrences and 16% cervical or internal mammary recurrences.

Radical mastectomy, a new standard of care: 20th century

The success of Halsted's radical mastectomy, which prevailed as the main surgical technique used in breast cancer into the mid-1970s, can be largely attributed to Halsted developing America's first training programme for surgeons. Prior to that time, surgeons had been largely self-taught. The residency programme, which helped to professionalise American surgery, again drew inspiration from Europe ‒ in particular the school that Bilroth had established in Vienna. At Johns Hopkins, Halsted developed a 'pyramid approach', where he first taught the technique to his chief residents, who then went on to supervise other residents. Eventually, 11 of Halsted's residents established their own surgical residency programmes, thereby spreading the concept of radical mastectomy across America and establishing it as the gold standard procedure.

In the UK, it was William Sampson Handley who was known as the proponent of radical mastectomy – as Gerald Kutcher writes, "In the UK, Handley was considered the seminal influence; for some in the British Isles, it was the Handley rather than the Halsted radical."

Undoubtedly, another factor for the popularity of radical mastectomy, writes medical historian Cordelia Shaw Bland, was that radical mastectomy was an intricate procedure that could only be performed by surgeons. The result was that radical mastectomy allowed surgeons to protect work from general practitioners (who at the time did many simple operations) and furthermore allowed them to charge higher fees reflecting the fact the operation took two to three hours, as opposed to one hour for simpler procedures.

Halsted's concept of radical mastectomy was strengthened by Janet Lane-Claypon, an English physician and statistician who published the first epidemiologic analysis of breast cancer surgical treatment, among other analyses that included risk factors. Commissioned by a newly formed cancer committee of the ministry of health, Lane-Claypon undertook a retrospective review of 20,000 surgical procedures, demonstrating a three year survival rate of 43% for women undergoing radical mastectomy versus 29% for those undergoing less extensive surgery, although she also was one of the first to apply staging criteria, finding that 65% to 80% of women with stage I disease were alive at three years. She looked too at lymph node involvement and her work seemed to confirm that early radical surgery before nodal effect was optimal, and her studies became influential in the UK, France and elsewhere.

The remarkable career of Lane-Claypon, considered a founder of epidemiology and the case-control study, was brought to an abrupt end in 1929 when, at the age of 52, she married and was forced to give up her job due to the English civil service not employing married women. See also this dissertation on her work, this article on 'a forgotten epidemiologic pioneer', and the book Preventive Strikes: women, precancer, and prophylactic surgery by Ilana Löwy.

Unspoken damage: 20th century

What Lane-Claypon's statistics failed to reflect was the terrible toll that mastectomy inflicted on surviving patients, who were often left with marked disabilities. "With the pectoralis major cut off, the shoulders caved inward as if in a perpetual shrug, making it impossible to move the arm forward or sideways. Removing the lymph nodes under the armpit often disrupted the flow of lymph, causing the arm to swell up with accumulated fluid like an elephant's leg, a condition… called surgical elephantiasis," wrote Siddhartha Mukherjee in The Emperor of All Maladies.

Disability was even more pronounced for those women exposed to more extreme forms of radical mastectomy (favoured by some of Halsted's followers), where the surgical technique evolved to include removal of ribs, collarbones, shoulders and even the upper arm 'en bloc' with the mastectomy specimen.

While Halsted's techniques can appear barbaric from modern medical perspectives, British breast surgeon Michael Baum said such views fail to reflect the medical limitations of the period. At a time when the majority of breast cancers presented as locally advanced (also without the benefits of radiotherapy or chemotherapy), he argued, radical mastectomy represented the best approach for achieving local control. "It allowed the woman to die of distant metastases, free of the ravages of uncontrolled breast cancer on her chest wall," Baum wrote in his book co-written with Craig Henderson, Classic Papers in Breast Disease.

Halsted had reasoned that, if local disease-free survival was improved by radical mastectomy, then overall survival benefits would surely follow. But as time progressed it became clear that radical mastectomy had no effect on the number of women who went on to develop metastasis.

Challenges to radical mastectomy: 1932 a key year

The first hint that the long-term effectiveness of radical mastectomy might not be as good as had been assumed came from a paper by Dean DeWitt Lewis and William Francis Rienhoff, two surgeons trained by Halsted. Their long-term follow-up of 950 patients treated by Halsted and his followers, published in Annals of Surgery in 1932, differed from Halsted's original reports by focusing on survival rather than local recurrence as a surrogate for cure. The paper showed survival rates (excluding perioperative deaths) at 3, 5, 10, 15, and 20 years were 46%, 24%, 8%, 4%, and 3% respectively, and that, where it could be accurately determined, breast cancer was the cause of death in 96% of patients.

"It became clear long-term survival of these patients wasn't much different from that of untreated patients in the same era," said Baum. But such findings received little publicity and it was some time before people started to question Halsted's underlying hypothesis.

Geoffrey Keynes, an English surgeon at St Bartholomew's Hospital, London, was undoubtedly ahead of his time, publishing one of the first papers advocating breast-conserving surgery supplemented by locoregional treatment from radium needles inserted throughout the breast and lymphatic fields draining the breast. Keyneshad come away from his experience as a field surgeon in the first world war with an aversion to unnecessary mutilation. For a time, Keynes (who was brother of the famous English economist John Maynard Keynes) advocated radical mastectomy. "But when it came to performing the operation myself, I found that it filled me with the utmost loathing and I soon became sceptical about its real efficiency," he wrote in his 1981 biography, The Gates of Memory (reviewed here), whose title plays to his other interest in the works of William Blake and other literary figures.

His proposed approach had been made possible by the discovery of X-rays by German physicist and mechanical engineer Wilhelm Conrad Röntgen, which marked the dawn of radiology and radiotherapy. Röntgen's discovery was published in 1895 ‒ the same year Halsted published his first results with radical mastectomy ‒ and was followed four years later with the discovery by Polish physicist Marie Curie and her French physicist husband Pierre Curie of radium as a source of radiation.

Keynes experimented first with treating women whose tumours were inoperable, exposing their breasts to radium crystals. After witnessing tumour regression, however, he started to use the radium in combination with conservative surgery.

In designing his approach, Keynes acknowledged the anatomic studies of his contemporary JH Gray at University College London, who had mapped the lymphatic system and provided a guide for areas of lymphatic drainage to irradiate. Keynes's probing of the Halsted dogma was further motivated by Gray's discovery in 1938 that 'lymphatic permeation' was rarely observed through lymphatic channels extending from the primary lesion to regional lymph nodes, and also the lack of lymphatic vessels on, or even approaching, the deep fascia of the pectoralis major muscle.

In 1932 Keynes published a paper describing 171 cases treated by excision of the primary tumour, with radium needles inserted into the breast, axilla, and supraclavicular fossa (high-energy external beam irradiation was not available at the time). Results showed that, for those treated three or more years earlier, 77.7% of those with class 1 tumours (defined as no palpable glands) were alive, 36.3% of those with class 2 tumours (with palpable glands) and 46.1% of those with class 3 tumours (defined as inoperable). These results compared favourably with a similar group treated at University College London with classic radical mastectomy.

Challenges to the lymph spread theory: 1930s–1940s

Keynes also questioned Halsted's basic assumption that breast cancer spread through localised lymph nodes, hypothesising that malignant cells entered the blood stream and spread throughout the body. "I was convinced that nothing I or anyone else did could affect more than marginally the ultimate survival rate," wrote Keynes in The Gates of Memory.

Keynes was taking a personal stand against what he described in his biography as "surgical malpractice – the performance of a grossly mutilating and illogical operation".

By 1939 Keynes had satisfied himself that the combination of local incision and radium needles was "as good as could be obtained by radical surgery", but with the advantage of lessened mutilation and avoidance of oedema of the arm. Sadly, Keynes' research was ultimately thwarted by the outbreak of the second world war, when radium was dispersed from the cities due to valid concerns about mass bombing, and advances in breast conservation were set back by almost 40 years. "Keynes' work still deserves the highest consideration for the clarity of his thought. Unfortunately, it was soon forgotten," said Marco Greco, head of breast surgery at the National Tumour Institute in Milan, Italy.

Keynes was also ahead of his time in systematically following up his patients and keeping extensive medical records. His meticulous notes enabled Reginald Murley, who had trained under Keynes, to perform a retrospective review of 1,044 breast cancer cases treated with various methods at St Bartholomew's Hospital between 1930 and 1939. The findings, published in 1953, showed no difference in 10 year survival rates between patients undergoing radical mastectomy, modified mastectomy and simple mastectomy. "Where efficient radiotherapy is available radical mastectomy should be abandoned in favour of conservative therapy," concluded the authors.

Such observations led to a groundswell of opinion against radical mastectomy in Europe, but did not prevent Halsted's vision from being perpetuated by his many followers in the US. Vincent DeVita, who headed the US National Cancer Institute from 1980 to 1988, later argued that the US surgical establishment had been united in their resistance to challenges to radical mastectomy, which they saw as a threat to their vested interests. The extent of the hostility, became clear in the late 1960s, when the American surgeon Bernard Fisher started questioning Halstedian principles, as DeVita recalled in an article in the BMJ. "The academic surgeons who worshipped Halsted were furious; to them, Bernie was attacking the sacred cow and he became the most hated surgeon on the planet. I have never seen doctors treated as badly as he was. It was stunning," said DeVita, who remembered how publication of Fisher's papers "could be held up for months as peer reviewers tried in vain to find fault".

In the UK, Keynes' championing of simple mastectomy passed to Robert McWhirter, a Scottish radiologist/radiotherapist at the Royal Edinburgh Infirmary who earlier in his career had worked alongside Keynes at St Bartholomew's Hospital. McWhirter persuaded his surgical colleagues in the south-eastern region of Scotland to perform lumpectomies on smaller lesions and simple mastectomies on larger ones. Additionally, McWhirter used external beam radiotherapy to the axilla, supraclavicular, and internal mammary lymph nodes (after the second world war high-voltage irradiation had gradually replaced radium needles). In 1948, McWhirter published five year survival rates for 757 patients with operable breast cancer treated with 'simple mastectomy' and radiotherapy. His 62% survival rate comparable favourably with that achieved by standard radical mastectomy at the time in the US.

"McWhirter's contribution was valuable in that it pointed out that a problem existed and had to be investigated," wrote John Hayward, a British breast surgeon, in 1974.

Modified mastectomy: 1940s–1960s

Also in 1948, surgeon David Patey at Middlesex Hospital, London, reported his alternative approach to reducing the morbidity of Halsted's procedure by preserving the pectoralis major muscle while still removing the pectoralis minor and lymph nodes. In his review of 18 mastectomies, performed between 1930 and 1943, Patey found no difference in survival or local recurrence between patients undergoing pectoralis major sparing operations and those having standard radical mastectomies. In addition to improved cosmetic results, Patey reported that the advantages of pectoralis major preservation included less blood loss and "a more suitable bed for skin grafting than ribs and costal cartilages".

"Although Patey's name is widely associated with modified radical mastectomy many others at the time also believed removing the pectoralis major not to be necessary. Patey has been given credit for the sole reason that his name has stuck," said Mike Dixon.

A further advance to modified mastectomy came from John Madden, a colleague of Patey, who in a paper published in 1972 emphasised preservation of both pectoral muscles, demonstrating that it was possible to clear the axilla and preserve the pectoralis minor's neurovascular supply. Madden's procedure has become the current standard used today in cases where a radical mastectomy is considered necessary. "The only reason surgeons removed the pectoralis minor muscle was to get to the axillary nodes. Madden and others worked out a way to preserve the muscle and still get the nodes out," explained Dixon.

As the evidence mounted against Halsted, important questions were raised by Diana Brinkley and John Haybittle who, working at Addenbrooke's Hospital, Cambridge, followed up long-term outcomes of breast cancer patients. In their analysis of subsequent causes of death of breast cancer patients seen in the Cambridge area from 1947 to 1950 they found that, 20 years on, deaths from breast cancer among those who had initially recovered from the disease were 16 times higher than age-matched controls. "This raised important questions about the curability of breast cancer by local therapy alone," said Baum.

But it was Umberto Veronesi in Italy and Bernard Fisher in the US who organised the large-scale trials that finally provided the definitive evidence against the practice of radical mastectomy. These studies, run independently in Italy and the US, ultimately led to a paradigm shift in the treatment of breast cancer surgery. Both the Italian and US teams showed that, while risk of local recurrences increases following breast conserving procedures, the extent of mastectomy has no influence on the woman's overall survival.

Veronesi's quadrantectomy ‒ developing the rationale and proof in the 1970s

Veronesi, a surgeon at the National Tumour Institute in Milan (who later founded the European School of Oncology and European Institute of Oncology), held the view that the 'minimum effective treatment', as opposed to the 'the maximum tolerable treatment' provided the best compromise for patients between achieving long-term survival and high quality of life. This life-view was first forged in his melanoma work, where he demonstrated that survival was identical for patients receiving a limited resection (1 cm) versus a wide excision (3 cm).

In his early career as a pathologist (prior to becoming a surgeon), Veronesi had experience of examining the entire breast tissue following radical mastectomy. "It became clear to Umberto that breast cancer originated in the lobules and disseminated along the ducts, but didn't invade other ducts. This led him to believe that, in breast surgery it was necessary to excise the entire portion of the ductal tree (right up to the nipple) that was involved by the carcinoma, but not all the other ducts," said Alberto Costa, a breast surgeon trained by Veronesi and the founding CEO of the European School of Oncology.

In 1969, Veronesi was one of 15 experts invited to attend a World Health Organisation meeting in Geneva, convened to evaluate methods of breast cancer diagnosis and treatment. At the meeting, Veronesi presented his proposal for a randomised trial comparing the traditional Halsted mastectomy with a conservative approach that maintained the radicality of a mastectomy (removal of skin, subcutaneous tissue, gland and fascia of the pectoral muscle), but only removing about one quarter of the breast (hence known as quadrantectomy). Additionally, surgery would be followed by radiotherapy. His overall aim was to achieve secure local control.

Randomisation of the trial, called Milan I, started in January 1973, with a total of 701 patients randomised to Halsted mastectomy (n=349) or quadrantectomy plus axillary dissection plus post-operative breast radiotherapy (n=352). Criteria for entry were for patients to have tumours measuring less than 2 cm and no palpable axillary nodes.

The first patient to volunteer, remembered Costa, was an actress who wanted to preserve her cleavage for the off-the-shoulder costumes she was required to wear in plays by Carlo Osvaldo Goldoni.

Recalling the surgical protocol, Costa said: "We would start the operation, send frozen sections to pathology, and if the result came back positive, telephone the data manager in charge of the book of randomisation tables. After consulting the list, she would tell us whether the patient should have radical mastectomy or quadrantectomy." If the selected treatment was quadrantectomy, the team would then need to alert one of four surgeons (including Veronesi), who had been specially trained to perform the new quadrantectomy technique. "In reality Umberto probably did half the operations," said Costa.

Results, published in the New England Journal of Medicine in 1981, demonstrated no difference in terms of local recurrence, disease-free survival or overall survival between the Halsted mastectomy and quadrantectomy.

A second important finding, of great significance for future studies, was that adjuvant radiotherapy did not have a carcinogenic effect. "One of the early worries about conservative treatment had been that doses of ionizing radiation sufficient to kill residual tumour cells would induce neoplastic transformation in the remaining breast tissue," wrote Costa and colleagues in 2001.

"This was the first ever study to demonstrate that excision of the tumour followed by radiotherapy gave equivalent results to mastectomy," said Mike Dixon. The major significance of Milan I as a mortal blow to radical mastectomy was quickly recognised, with the study making front page news in the New York Times.

The Milan I update, with a 20-year follow-up, confirmed preliminary findings, and established the concept of breast conserving surgery as the standard of care.

About a year into the Milan trial, Umberto Veronesi's confidence was severely tested by publication of the first randomised controlled study of breast conservation therapy, which demonstrated a negative result. The study, by John Hayward (1923–2013) from Guy's Hospital, London, compared Halsted mastectomy plus radiotherapy to the regional lymph nodes, with wide resection of the tumour followed by radiotherapy to the breast, supraclavicular axillary and internal mammary lymph nodes. Results published in 1974 showed that local recurrence was much higher in the group treated conservatively.

"An important aspect of the Guy's study is that the conservative treatment adopted would not be considered adequate today. First because axillary dissection was not performed – even when there was clinical evidence of metastatic involvement – and second because the radiotherapy dose (32 Gy) was too low to eradicate residual local disease," wrote Costa and colleagues.

Veronesi was well aware of publication of the trial. "It left him puzzled and with many doubts. But due to his courage and great faith in his convictions, he took the decision to continue," said Marco Greco, a breast surgeon who worked with Veronesi at the time.

Fisher's lumpectomy: developing the rationale and proof

In the US, Bernard ('Bernie') Fisher, at the University of Pittsburgh, was undertaking parallel studies that added valuable support to Veronesi's findings. Fisher's initial interest in performing breast-conserving procedures came from laboratory observations in mice. Working with his pathologist brother, Edwin Fisher, from 1965 to 1967, Fisher tracked radioactive tumour cells in mice and demonstrated that regional lymph nodes had no filtration capacity, and furthermore they showed that cancer cells could bypass the nodes via lympho-venous channels or direct invasion of the venous system.

See these papers by the pair: Transmigration of lymph nodes by tumor cells; Barrier function of lymph node to tumor cells and erythrocytes I, Normal nodes; Barrier function of lymph node to tumor cells and erythrocytes II. Effect of X-ray, inflammation, sensitization and tumor growth.

From these observations Bernie Fisher developed his hypothetical model of 'biological predeterminism', stating that outcomes of treatment for early breast cancer were determined by the burden of micro-metastases present at time of diagnosis. Such views challenged the prevailing paradigm of centrifugal spread (promoted by Virchow and Halsted) that cancer cells spread along major tissue lines and in the lymphatic system.

Instead, Fisher suggested that from the outset breast cancer was a systemic disease and that distant metastases were present well before diagnosis in the majority of cases, implying that Halsted mastectomy was a worthless procedure. "The findings led us to conclude that patterns of tumour spread are not solely dictated by anatomical considerations but are influenced by intrinsic factors in tumour cells and in the organs to which they gain access," recalled Fisher in his Karnofsky memorial lecture in 1980. Lymph nodes, Fisher argued, did not 'seed' distant metastases, but simply reflected the general success of metastatic cells in any given patient.

"Bernie became famous for saying radical mastectomy was like shutting the stable door after the horse had bolted," recalls Michael Baum. The justification for breast conserving surgery was that, if the cancer had already spread, radical mastectomy would have no influence whatsoever on survival, and that less radical surgery was likely to achieve similar outcomes.

In 1967, when Fisher was appointed chair of the National Surgical Adjuvant Breast and Bowel Project (NSABP), the US clinical trials cooperative group, he had the opportunity to start testing his hypothesis in clinical trials. In 1976, Fisher's NSABP B-06 trial started randomising patients with tumours up to 4 cm to total mastectomy, lumpectomy alone, or lumpectomy with breast radiotherapy. Results showed that overall survival and disease-free survival were similar between the three groups, but that radiotherapy reduced breast cancer recurrence rates after lumpectomy.

See: Five-year results of a randomized clinical trial comparing total mastectomy and segmental mastectomy with or without radiation in the treatment of breast cancer; Eight-year results of a randomized clinical trial comparing total mastectomy and lumpectomy with or without irradiation in the treatment of breast cancer; Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer.

In a US surgical climate that was still dominated by Halsted, Fisher, who did multicentre trials faced a considerable challenge recruiting open-minded surgeons to perform his technique. To enrol sufficient patients he became like a travelling salesman, making pitches at small clinics and meetings of community doctors around the US.

"There was great fear that they were actually committing malpractice by doing anything less than radical mastectomy. And hospital boards of surgery were very reluctant to consider anything less than radical mastectomy. It was tantamount to heresy," recalled Fisher in an interview.

Triumph of breast-conserving approaches to breast cancer

The trials of Veronesi and Fisher published in the 1970s and early 1980s changed breast cancer surgery, pointing the way to 'less surgery' and consigning mutilating radical mastectomy to the past. The studies also confirmed the hypothesis that breast cancer prognosis was linked to the presence or absence of distant metastasis, and changes in local treatment exerted no effect on overall survival.

"The fundamental difference between Fisher and Veronesi was that Fisher considered breast cancer to be a systemic disease from the outset, while Veronesi believed that local control with surgery and radiotherapy to be equally important," said Greco.

There were also differences in the surgical techniques they used. Veronesi's technique involved removal of the entire quadrant of the breast containing the primary tumour, the overlying skin and fascia of the pectoralis major muscle, while Fisher undertook a segmental mastectomy, where patients were operated on with 1 cm margins around the tumour.

The question about the extent of breast conservation was addressed by Veronesi in the Milan II trial. Between 1985 and 1987, 705 patients with tumours of less than 2.5 cm were randomised to either quadrantectomy or lumpectomy, with all patients undergoing axillary dissection and radiotherapy. In quadrantectomy, 2–3 cm of normal tissue surrounding the tumour were excised, as well as the overlying skin and the underlying fascia, while in lumpectomy a rim of 1 cm around the tumour was removed. After 10 year follow-up, results showed rates of overall survival and distant metastasis were the same in both groups, but breast tumour recurrence was significantly higher in the lumpectomy group.

"Over the years, the differences between Veronesi and Fisher's approaches progressively diminished until conservative breast surgery became uniform," said Greco.

The Milan III trial explored the role of radiotherapy. Between 1987 and 1989, 567 women with tumours measuring less than 2.5 cm were randomised to quadrantectomy with axillary dissection with or without adjuvant radiotherapy. Results showed that the radiotherapy group had a significantly lower recurrence rate, but that five-year overall survival rates were comparable.

The end for radical mastectomy was sounded by Rose Kushner, a campaigning US journalist who orchestrated a public relations campaign against Halsted mastectomy, informing women about surgical alternatives. When Kushner was diagnosed with breast cancer in 1974, she made 18 telephone calls before finding a surgeon willing to perform a modified radical mastectomy.

After travelling to Europe to learn about conservative breast cancer treatment, Kushner observed that breast cancer surgery was not as extensive in countries where there are more women practising medicine than in the US. Bruce Chabner, a director at the US National Cancer Institute in Bethesda, Maryland, credited Kushner with being the most important person leading the major change in breast surgery. "I don't think the public would have accepted it or even known about it if she had not been so persistent in her efforts," he told the Los Angeles Times.

Kushner wrote a book, Why Me? What Every Woman Should Know About Breast Cancer to Save Her Life, and this and other contributions are noted on her Wikipedia page.

The final turning point against radical mastectomy came in 1979, when the US National Institutes of Health (NIH) held a conference on breast cancer treatment, where a consensus panel concluded radical mastectomy was no longer appropriate and that smaller operations combined with radiotherapy, chemotherapy, or both provided equivalent survival with less disfigurement.

As the information percolated through to mainstream breast surgeons, the proportion of breast cancer patients in the US receiving mastectomy gradually declined. In 1988 77% of patients were still receiving full mastectomy; by 2004 that had dropped to 38%.

In European countries, data from the European Society of Breast Cancer Specialists (EUSOMA) on Italy, Belgium, Germany and Switzerland showed that by 2010 only 18.6% of women treated surgically for early-stage disease received mastectomy.

Today, breast-conserving surgery is recommended by guidelines if clear resection of margins can be achieved and if the ratio between tumour size and breast volume is appropriate, with an explicit distance of 1 mm from all sides of the tumour recommended.

And owing to the widespread introduction of mammography screening programmes from the 1980s onwards, the average size of invasive tumours decreased, allowing breast conservation therapy to be appropriate for 50% to 70% of patients.

Extending the concept

To expand the indication of conservation surgery to larger tumours, Veronesi proposed neoadjuvant chemotherapy, with or without radiotherapy, to reduce tumour size. Working with Gianni Bonadonna, the pioneer of chemotherapy in breast cancer, Veronesi and other colleagues gave preoperative chemotherapy to 226 women with tumours up to 3 cm in size. Results showed that the addition of preoperative chemotherapy permitted conservative surgery in 90% of cases, and did not depend on the chemotherapy regimen used.

And as noted, Veronesi also led the development of sentinel lymph node biopsy (SLNB) and radioguided occult lesion localisation (ROLL).