I need a paper not too long about 6 pages only, I have started but it needs more development as the professor ask for it. I need to provide a thesis statement and the paper need to be documented properly MLA style I have turtinent it 

1

The story of breast cancer is told in the acts and arti-
facts of the human struggle against disease. It is an
epic tale that follows the concepts of illness from the
work of evil spirits or of offended gods to the results
of identifiable physical causes, and the healing arts
from mysticism to the tools of modern science. The
following is a brief history of breast cancer in the
Western world.

PREHISTORY AND THE ANCIENT WORLD

Prior to recorded history, life was undoubtedly short,
and as cancer is predominantly a disease of maturity
one suspects that cancer was a poor competitor
among causes of mortality. The study of primitive
peoples indicates that for the ill, rituals, potions, and
recipes at the hands of magicians, witch doctors, and
folk healers were the usual recourses. In ancient
Babylon (2100–689 BC) it was common practice to
place the ailing in public places for the recommen-
dations of passersby, but professional healers were
also recognized. The Code of Hammurabi, inscribed
on a pillar in Babylon, indicated that healers were
paid fees for their services and were penalized for
surgical deaths with amputation of their hands.1

Before the third millennium BC, physicians had
learned the futility of treating certain tumors of the
breast. Among the eight extant Egyptian medical
papyri, The Edwin Smith Surgical Papyrus is
believed to contain the first reference to breast can-
cer (Figure 1–1). This surgical text, penned in hier-
atic script, is the incomplete and fragmented copy of
an original document that probably dates back to the
pyramid age of Egypt (3000–2500 BC) and was pos-

sibly written by Imhotep, the physician-architect who
practiced medicine and designed the step pyramid in
Egypt in the 30th century BC.2 It provides the earli-
est references to suturing of wounds and to cauteri-
zation with fire drills. More pertinently, it includes
the diagnosis and treatment of eight cases of ailments
of the “breast,” meaning of the bones and soft tissues

1

History of Breast Cancer
WILLIAM L. DONEGAN

Figure 1–1. Column VIII of The Edwin Smith Surgical Papyrus, a
copy of the first document believed to describe cancer of the
breast, circa 3000 BC. Used with permission from The Classics of
Surgery Library.2

2

BREAST CANCER

of the anterior thorax, all in men and most due to
injuries. One of the five cases relating to soft tissues
(Case 45) describes “bulging tumors” in the breast.
The author writes that if the tumors have spread over
the breast, are cool to the touch, and are bulging,
there is no treatment. Whether this case was a rare
cancer of the male breast is conjectural, but in stark
contrast to the physician’s active recommendations
for the other cases, he recognized this one as sinister;
and his conviction that no treatment would help
appears to have been based on established practice.

GREEK AND ROMAN PERIOD
(460 BC–475 AD)

Ancient Greece was pervaded by a rich mythology
based on a belief in close associations between
humans and gods. Historians speculate that the god
of medicine, Aesculapius, may have had origin in a
physician who lived around the time of the siege
of Troy (≈1300 BC) and to whom were attributed
miracles of healing. In the Iliad, Homer mentioned
Aesculapius’ two sons as “good physicians” who
had come to join the siege.3 On the seal of the Amer-
ican College of Surgeons, Aesculapius is pictured
seated, holding his staff entwined with a serpent, the
symbol of life and wisdom. Early Greeks sought
cures by sleeping in the abaton at the temples of
Aesculapius and enjoying the associated baths and
recreations, forerunners of modern health spas.
Votive offerings in the form of breasts found at such
sites offer evidence that some came hoping for cure
of breast disease (Figure 1–2).

Greek medicine and surgery became the most
sophisticated of its time. In the course of his con-
quests, Alexander the Great of Macedonia (356–323
BC) founded the city of Alexandria on the Nile delta
in 332 BC, and a famous medical school arose there
around 300 BC. The library at Alexandria was the
largest of its time, housing more than 700,000 scrolls.
Many prominent Greek and Roman physicians stud-
ied, taught, and practiced in Alexandria. The study of
anatomy was based on dissection of human bodies
and surgery flourished; vascular ligatures were used.

Physicians of the Hellenistic period provide
vivid accounts of breast cancer. The Greek term
“karkinoma” was used to describe malignant

growths and “scirrhous” to describe particularly
hard, solid tumors. “Cacoethes” referred to an early
or a probable malignancy. A “hidden” cancer was
one not ulcerating the skin. In an anecdote,
Herodotus (484–425 BC), historian of the wars
between Greece and Persia, claimed that Demo-
cedes, a Persian physician living in Greece, cured
the wife of Persian King Darius of a breast tumor
that had ulcerated and spread.

Hippocrates (460–375 BC), whose legacy, the
Corpus Hippocraticum, may have been the work of
more than one person, was the most prominent of
Greek physicians. He maintained that every disease
was distinctive and arose from natural causes, not
from gods or spirits.4 He also believed in the power of
nature to heal and in a humoral origin of disease. In
his view, a balance of the four bodily fluids, blood,
phlegm, yellow bile, and black bile (later linked to
sanguine, phlegmatic, choleric, and melancholy dis-
positions by Galen) was necessary for good health.
Hippocrates described cases of breast cancer in detail.
One of his case histories was of a woman of Abdera
who had a carcinoma of the breast with bloody dis-
charge from her nipple. Attaching a beneficial effect
to the bleeding, he noted that when the discharge
stopped, she died. Similarly, Hippocrates associated
cessation of menstrual bleeding with breast cancer
and sought to restore menstruation in young sufferers.
His detailed description of the inexorable course of
advancing breast cancer rings true today. He said that

Figure 1–2. Votive offerings from an Etruscan temple include a
vagina, a uterus, an ear, an eye, and a breast (lower central). Repro-
duced with permission from Lyons AS and Petrucelli RJ.6

History of Breast Cancer 3

hard tumors appear in the breast, become increasingly
firm, contain no pus, and spread to other parts of the
body. As the disease progresses, the patient develops
bitter taste, refuses food, develops pain that shoots
from the breast to the neck and shoulder blades, com-
plains of thirst, and becomes emaciated. From this
point death was certain. He advised no treatment for
hidden breast cancers because treatment was futile
and shortened the patient’s life.

In the ascendant Roman Empire, physicians were
guided largely by Greek medicine. Around 30 AD, the
Roman physician Aulus Cornelius Celsus (42 BC–37
AD) noted that the breasts of women were frequent
sites of cancer. Celsus described breast cancer in his
manuscript, De Medicina, and defined four stages.
The first was cacoethes, followed by carcinoma with-
out skin ulceration, carcinoma with ulceration, and,
finally, “thymium,” an advanced exophytic and some-
times bleeding lesion, the appearance of which sug-
gested to him the flowers of thyme. Celsus recom-
mended excision for the cacoethes but no treatment
for other stages. In situations of uncertainty, the tumor
was treated first with caustics, and if the symptoms
improved, it was a cacoethes; if they worsened, it was
a carcinoma. Some masses for which treatment was
successful might have been fibroadenomas, phyl-
lodes tumors, or even tuberculosis.

Leonides, a surgeon of the Alexandrian school,
described surgical removal of breast cancers during
this time.4 Leonides said that with the patient supine
he cut into the sound part of the breast and used a
technique of alternately cutting and cauterizing with
hot irons to control bleeding. The resection was car-
ried through normal tissues wide of the tumor and
customized to the extent of involvement. The opera-
tion was concluded with a general cauterization to
destroy any residual disease. Poultices were then
applied to the wound to promote healing. He
explained that excision was used selectively for
tumors in the upper part of the breast of limited
extent, and he specifically advised against surgery if
the whole breast was hardened or if the tumor was
fixed to the chest wall. Leonides was perhaps the
first to record that breast cancers spread to the
axilla. Complete and thorough excision of breast
malignancies has been a cardinal principle of
surgery since the time of Leonides.

The teachings of the Greek physician, Galen of
Pergamum (129–200 BC), on the subject of breast
cancer reached far beyond his time. Born of a
wealthy and educated family in Asia Minor, he
traveled and studied widely. Galen became sur-
geon to gladiators in Pergamum and finally prac-
ticed in Rome, attending the emperor Marcus
Aurelius. His vast experience, clinical acumen,
investigative approach to knowledge, and prolific,
authoritative writings (400 treatises) gained Galen
enormous respect. For the next 1,500 years,
Galen’s teachings guided medical practice, and his
animal dissections provided the bases for human
anatomy and physiology.

Galen revered Hippocrates and adopted his
humoral theory of disease. In Galen’s view, breast
cancer was a systemic disease caused by an excess of
black bile in the blood (ie, melancholia). Black bile
was formed in the liver from blood elements and
absorbed in the spleen; malfunction of either of these
organs caused an excess of black bile, which thick-
ened the blood, and where black bile accumulated,
carcinoma developed as hard, non-tender tumors that
ulcerated if the bile was particularly acrid. Like Hip-
pocrates, he noted that carcinomas were predisposed
to accumulate in the breasts of women who had
ceased to menstruate, a recurring theme and doubt-
less a reference to the frequency of cancer in post-
menopausal women. This observation supported
Galen’s belief that menstruation, and the practice of
bleeding, served to clear the body of excess black
bile. He likened the dilated veins that radiated from
carcinomas to the legs of a crab; as a result, the crab
became a symbol for cancer. Leonides had also
likened cancers to crabs, but rather because the tena-
cious adherence to surrounding tissues mimicked the
crab’s pinchers. For early cancers, Galen recom-
mended purging, bleeding, diet, and topicals. Ulcer-
ating cancers were treated with caustics or cleansed
and treated with zinc oxide.

In operating for breast cancer, Galen’s approach
was less modern than that of Leonides before him.
Galen condemned the use of ligatures, and although
he was aware of the dangers of excessive blood loss,
he preferred to let the blood run unchecked and to
express the dark, dilated veins in order to rid them of
the morbid black bile. The cancer was removed at

4 BREAST CANCER

the boundary between diseased and healthy parts,
sparing the cautery out of concern for destroying too
much tissue. After Galen, medicine languished into
a contented observance of his teachings, and the
Middle Ages intervened, temporarily halting further
medical progress.

MIDDLE AGES (476–1500 AD)

The Middle Ages, a period of roughly 1,000 years,
began with the collapse of the Roman Empire in 476
and ended with the Renaissance and discovery of the
New World in 1492. With the Middle Ages came
feudalism, bubonic plague, crusades, and the age of
faith. Papal influence spread in the form of the Holy
Roman Empire, and human dissection was prohib-
ited by Papal decree; opposition to church doctrine
constituted heresy. To save his soul, the astronomer
Copernicus (1473–1543 AD) was forced to rescind
his thesis that the earth circled the sun rather than
the reverse, and the physician Michael Servetus
(1511–1553), discoverer of the pulmonary circula-
tion, was burned alive for heresy. Meanwhile,
monastic scribes in Christian Europe quietly pre-
served medical knowledge, principally that of
Galen, by copying and illuminating surviving
ancient manuscripts, manuscripts that were in little
demand during an era of widespread illiteracy.
Monks dispensed folk remedies, and surgery was
discouraged. Amputation of the breast was depicted
by the church as a form of torture in the story of
St. Agatha, the patron saint of breast disease5 (Fig-
ure 1–3). Many miraculous cures were attributed to
saints. Faith healing by the laying on of hands was
among the remedies, a practice that endured to
recent times. Folk medicine included application of
fresh bisected puppies and cats.

After the death of the prophet Muhammad
(570–632 AD), the rise of Islam resulted in the Arab
conquest of the southern shores of the Mediterranean
from Persia to Spain, bringing to an end the medical
center in Alexandria. Medical documents that sur-
vived were translated into Arabic for study and pre-
served; translated later from Arabic into Latin, the
language of medicine in Europe, they re-entered the
continent. In addition to preserving the past, Arabic
medicine was noted for expertise in pharmacy and

for establishing fine hospitals. Among the most
influential physicians of this period were Avicenna
(980–1037 AD), the Jewish physician Maimonides
(1135–1204 AD) and Albucasis (936–1013).6 Avi-
cenna’s reputation rivaled that of Galen, but he had
no new insights about breast cancer. Albucasis in
Moorish Spain favored the cautery and caustic appli-
cations for treatment of breast cancer but admitted
that he had never cured a case of breast cancer and
knew of no one who had. Caustic paste (a mixture of
zinc chloride, stibnite, and Sanguinaria canadensis)
was used for treatment of breast cancer in the United
States as late as the 1950s.7 The paste was applied to
the involved breast to cause progressive tissue necro-
sis, which was then cut away or allowed to slough
and to heal by granulation. Continued use of charms,
prayers, medicaments, and caustics in conjunction
with surgery and modern methods is a reminder that
treatments for breast cancer progressed through his-
tory not by substitution, but by addition.

Figure 1–3. Saint Agatha, the patron saint of breast disease, was
martyred for her Christian beliefs. Her torture included amputation of
the breasts shown here in a painting by Anthony Van Dyck.5

History of Breast Cancer 5

In the late Middle Ages, Henri de Mondeville
(1260–1320 AD), surgeon to the king of France,
refined Galen’s black bile theory with a distinction
between black bile from the liver, which caused a
hard tumor in the breast (a sclerosis), and twice
combusted black bile derived from breakdown of the
other three other body humors, which caused a true
cancer. He described true breast cancer as ulcerated
with thick margins and having an offensive odor.
The treatment: diet and purging, with operation only
if the cancer could be completely excised; de Mon-
deville appreciated that incomplete removal often
resulted in a non-healing wound.8

RENAISSANCE (SIXTEENTH
TO EIGHTEENTH CENTURIES)

The Middle Ages ended with the Renaissance. This
period of approximately 200 years, also known as
The Enlightenment, saw a rejection of medieval val-
ues and a rebirth of interest in secular art, in science,
and in exploration of the world and the human body.
With the Renaissance came badly needed formal
training for physicians. The University of Salerno,
founded around 1200 AD, was the first organized
medical school in Europe. Free of clerical influence
and progressive for its time, Salerno served as the
precursor of prominent schools of medicine in
France, England, and elsewhere on the continent.
The Royal College of Physicians was established in
London in 1518, and the first medical journal, the
Ephemerides, appeared in 1670.

Surgeons became more respectable. Tradition-
ally unlettered craftsmen whose operations were
directed by physicians, surgeons became indepen-
dent practitioners. Incorporated as barber-surgeons
in England since 1461, surgeons were officially
separated from barber guilds in 1745. The French
Academie de Chirurgie, established in 1731, pro-
duced the first journal for surgeons, Memoires,
which in 1757 published Henri LeDran’s thesis that
breast cancer had a local origin, providing an impe-
tus for surgical cure.9

The Renaissance in medicine brought a critical
reexamination of anatomy and physiology and a
decline of Galen’s authority. Publication of
Andreas Vesalius’s De Humani Corporis Fabrica in

1543 marked the beginning. This volume of
anatomical drawings, based on the young professor
of surgery at Padua’s own dissections of human
cadavers, illustrated the errors of Galen’s anatomy
and stimulated further interest in human anatomy.10

The Fabrica provided no useful details of the
female breast. However, 300 years later, Sir Astley
P. Cooper (1768–1841), surgeon to Guy’s Hospital
in London, illustrated with desiccated specimens
the suspensory ligaments of the breast that bear his
name. The Parisian anatomist Marie-Philibert-Con-
stant Sappey (1810–1896) illustrated the lymphat-
ics of the breast, a name that endures as Sappey’s
subareolar plexus.11,12

Each anatomic discovery generated new theories
about breast cancer, but to little advantage. John
Hunter (1728–1793), the father of investigative
surgery, conceived that coagulation of lymph rather
than black bile was responsible for carcinoma of the
breast and the associated cancerous nodes. Boer-
haave of Leyden (1668–1738) postulated that neural
fluid “liquor nervorum” might be the instigator of
breast cancer, whereas others believed that inspis-
sated milk within the mammary ducts generated
cancers. Trauma to the breast was believed to cause
leakage into the tissues, which created irritation,
induration, and malignant change. Observing the
rapid growth of ulcerating breast cancers, Claude-
Nicholas le Cat (1700–1768) in Rouen postulated
that exposure to air was a stimulant to cancers, a
tenacious idea persisting in some laity today. Anec-
dotes of multiple-affected family members sup-
ported the suspicion that breast cancer was infec-
tious long before the hereditary aspect of the disease
became known in the twentieth century. The deadly
spread of malignancy was attributed to circulating
humors or to a general diathesis. The suspicion of a
“cancer prone” personality lingers but remains
unconfirmed by modern psychological research.13

Breast lumps continued to fuel controversy
about the nature of a “schirrous,” the hard tumor that
generated concern for patient and physician.
Whether schirrous was benign, a stage of cancer, or
a precursor that became cancer by a process of
“acrimony” remained in doubt. Observation or
immediate treatment divided opinions. Opinions on
the worth of surgery varied. Extended survival of

6 BREAST CANCER

occasional untreated cases, coupled with the consid-
erable risk and poor results of mastectomy, sup-
ported a nihilistic attitude among many physicians.
Others shared the opinion of Nicolaes Tulp
(1593–1674) of Amsterdam, who saw the need for
early surgery. “The sole remedy is a timely operation,”
he said.4 For the most part, the fearsome prospect of
an operation was delayed until bulky growth, pain,
or ulceration made obvious both the diagnosis and
the need. Informed surgeons recognized tumor attach-
ment to the chest wall, sternal pain due to deep inva-
sion or involvement of the internal mammary nodes
(described by Petrus Camper in 1777), poor general
health, or a diathesis-revealing “melancholy” appear-
ance as contraindications to mastectomy.

Without anesthesia or antisepsis, mastectomies
were a painful and dangerous ordeal customarily car-
ried out in the patient’s home. The procedure varied
from impalement of the breast with needles and
ropes for traction followed by swift amputation
through the base, leaving a large open wound as illus-
trated by Johann Scultetus (1595–1645) in his Arma-
mentarium Chirurgicum, to the alternative of incis-
ing the skin and enucleating the tumor by hand.4 The
prevailing opinion was to leave the wound open to
minimize the risk of infection. From 2 to 10 minutes
were required for the operation, depending on the
technique. Ligatures, if used, were led out through
the wound to be withdrawn later, after necrosis or
infection loosened them. Painful re-explorations of
the wound on subsequent days were performed to
inspect for infection or to remove additional tumor;
the major threats were secondary hemorrhage or
potentially fatal infection. In various illustrations, the
patient’s hands were tied behind her back or assis-
tants restrained her while another assistant caught
jets of blood in a pan. A cauterizing iron provided
hemostasis, and steam issued from the wound where
it seared the flesh. The company included a dour,
attending physician and often an anguished family
standing in witness. Students of breast cancer should
not miss the touching account of such an operation in
Scotland told by John Brown.14 The rigors of surgery
were such that alternative treatment with compres-
sion of the breast using metal plates or strapping, not
entirely devoid of pain and occasional necrosis, con-
tinued to survive into the nineteenth century.

Expert surgeons operating in major centers dur-
ing these times enlarged mastectomies to include all
morbid parts. In Paris, Jean Louis Petit (1674–1750)
removed both the breast and diseased nodes in his
operations, and in 1774, Bernhard Perilhe reported
removing the pectoralis major muscle as well. A
healed wound was the customary end point for
declaring a surgeon’s success; few bothered with
further follow-up. In a report by Richard Wiseman
(1622–1676), surgeon to Charles II, among twelve
mastectomies, two patients (17%) died from the
operation, eight died shortly afterwards from pro-
gressive cancer, and two of the 12 were declared
“cured” for undisclosed lengths of time.4

NINETEENTH CENTURY

From the oncologic standpoint, the nineteenth cen-
tury was truly a giant step forward. Major advances
were made in human pathology and in the safety of
surgery. Hand washing was promoted by the Hun-
garian physician Ignac Semmelweis (1818–1865)
and by Oliver Wendell Holmes, MD (1809–1894),
Professor of Anatomy and Physiology at Harvard
University. Building on Louis Pasteur’s (1822–1895)
discovery of “putrefying” bacteria, Joseph Lister
(1827–1912) in Glasgow introduced surgical anti-
sepsis with carbolic acid spray in 1867.15 Adoption
of aseptic techniques (ie, steam sterilization) first by
Ernst von Bergmann of Berlin in 1886, the surgical
mask by the Pole Johannes von Mikuliez-Radecki in
1886, and sterile rubber surgical gloves by William
S. Halsted in 1890 further reduced contamination.16

Successful demonstration of general anesthesia by
William T. Morton in Boston in 1846 allowed
unprecedented development of surgery; operations
became more acceptable, and for the first time sur-
geons could concentrate on precision rather than
haste. Blood transfusions became safe after 1900
when Karl Landsteiner in Austria discovered blood
groups. All of the current technology for treatment
of breast cancer had their beginnings in this century;
only chemotherapy remained for development in the
years to come.

The microscope was the key to progress in
pathology. Building on Anton van Leewenhoek’s
(1674–1723) work with lenses, perfection of the com-

History of Breast Cancer 7

pound achromatic microscope in Germany opened
the world of microscopic anatomy, and Germany was
the center of this new science under the leadership of
Johannes Müller at the University of Berlin.

Early in the century, the microscopic work of
Matthias Schleiden (1804–1881), a botanist at the
University of Jena, and of Theodor Schwann
(1810–1882), working in Müller’s laboratory, estab-
lished that both plants and animals were composed of
living cells with the nucleus as the essential feature.
Robert Hooke (1655–1703) earlier had coined the
word “cell” from the structure he saw in cork. “The
cells are organisms,” said Schwann, “and animals as
well as plants are aggregates of these organisms…”
These two researchers destroyed the existing humoral
and the competing solidistic concepts of tissue com-
position. Johannes Müller (1801–1859) was first to
report that cancers also were composed of living cells.
In his landmark publication of 1838, Uber den feinen
Bau und die Formen der krankhaften Geschwülste,
Müller noted the similarity of cells in a “scirrhus” of
the breast and its metastases in the ribs and noted that
cancer cells had lost the proportions of normal cells17

(Figure 1–4). Rudolph Virchow, also of Berlin,
Müller’s former student and the founder of cellular
pathology, is responsible for the dictum that “all cells
come from cells.” His lectures, Die Cellularpatholo-
gie, published in 1858, laid to rest the notion of spon-
taneous generation of living cells from a liquid
“blastema.” But Virchow did not make the connection
between migrating malignant cells and metastases; he
thought that axillary metastases arose from cells in
the nodes responding to “hurtful ingredients” or “poi-
sonous matter” from the cancer in the breast.18 Müller
was perhaps the first to suspect that spread of malig-
nant cells constituted the mechanism of metastasis,
later confirmed by the microscopic work of Carl
Thiersch (1822–1895) and Wilhelm von Waldeyer
(1836–1921).4 These insights supported the concept
that breast cancer spread from a local origin.

Noteworthy clinical observations were also being
made. Alfred Velpeau was the first to describe breast
cancer en cuirasse, the deadly form that spreads
across the chest like a breast plate.19 Velpeau’s Traite
des maladies du sein, published in 1854, was a com-
prehensive review of breast disease of the time.
Across the English Channel in London, Sir James

Paget made a brief (1,050 words) but enduring report
in 1874 describing changes on the nipple that pre-
ceded breast cancer and continue to bear his name.
He said, “… certain chronic affections of the skin of
the nipple and areola are very often succeeded by the
formation of sirrhous cancer in the mammary
gland…within at the most two years, and usually
within one year.”20 Paget’s observation remains as
valuable today as when it was first made.

Charles Moore (1821–1870) at the Middlesex
Hospital in London deserves credit for the en bloc
principle of resection. Moore was convinced that the
piecemeal mastectomies of his day spread the “ele-
ments” of cancer in the surgical wound and
accounted for the local reappearance of cancer in, or
adjacent to, the scar. In 1867 he published a strong
argument for removal of the whole breast intact in
every case.21 He also recommended removal of axil-
lary nodes and the pectoral muscles if they were
involved. William M. Banks in Liverpool carried
mastectomy a step further in 1882 by practicing rou-
tine removal of axillary lymph nodes.22

Similar initiatives were occurring in Germany.
Ernst G.F. Küster (1839–1922) in Berlin was per-
forming routine axillary clearance and reported that
it virtually eliminated recurrences in the axilla. In
1875 Richard von Volkmann (1830–1889) was rou-
tinely removing the pectoralis major fascia, and
Küster’s assistant Lothar Heidenhain (1860–1940)
held the muscle itself suspect. Their microscopic
studies of mastectomy specimens showed extension

Figure 1–4. Figure 9, Table I, from Johannes Müller’s Uber den
feinen Bau und der Formen dei Krankhafte Geschwülste, 1838, illus-
trating for the first time the cellular structure of breast cancer. Repro-
duced from Müller J.17

8 BREAST CANCER

of cancer to the deep pectoral fascia, and occasion-
ally to the muscle itself, when it had not been sus-
pected. Samuel W. Gross at Jefferson Medical Col-
lege in Philadelphia (1837–1879) attributed a
3-year survival of 19.4% to routinely removing not
only the whole breast but the pectoralis fascia and
axillary contents.4

The events in Germany influenced William S.
Halsted (1852–1922), Professor of Surgery at Johns
Hopkins Hospital in Baltimore, to devise what
became known as the radical mastectomy. He
reported the operation in 1894 almost simultane-
ously with a similar report by Willy Meyer in New
York.23 Through a large “tear-drop” incision, Hal-
sted removed en bloc the breast complete with its
skin, the axillary lymph nodes, “a part, at least” of
the pectoralis major muscle (the sternal portion) and
“usually” cleared the supraclavicular region. Halsted
had adopted this “complete” operation 5 years ear-
lier, and emphasized that the pectoralis major mus-
cle must be removed in all cases to obtain a secure
tumor-free deep surgical margin. He explained that
von Volkmann had removed the pectoral muscles in
38 cases with reduction in local recurrences. As
Moore before him, Halsted wrote that the crux of the
operation was “to remove in one piece all of the sus-
pected tissues” lest the wound become infected by
the division of tissues or lymphatics invaded by the
disease, and lest shreds or pieces of cancerous tissue
be overlooked in a piecemeal extirpation. It is clear
from Halsted’s descriptions that the supraclavicular
clearance initially was a removal of tissues superior
to the axillary vessels in the course of the axillary
dissection, later a formal dissection through a cervi-
cal incision and ultimately an excursion that he
abandoned. The complete operation resulted in a
large open wound left to heal by granulation. Two
years later he began to close the wound with a split-
thickness skin graft, a technique developed by
Thiersch (Figure 1–5). Eventually primary closure
of skin became more popular.

Whether radical mastectomy resulted in
improved local control is unclear. Halsted recog-
nized “local” as recurrences in the surgical area
within 3 years of operation (6% in his cases);
“regionary” recurrences, by his definition, appeared
after 3 years or in the skin away from the scar. The

German literature did not distinguish local from
regionary recurrences. By counting both, and mak-
ing the unlikely assumptions that cases were compa-
rable and had equal periods of follow-up, his recur-
rence rate was 20% compared to 55 to 82% for his
German counterparts. Halsted disregarded that local
and/or regionary recurrences totaled 58% when von
Volkmann had removed the pectoralis major muscle
and 60% when he had not, a negligible difference.

Halsted had no surgical deaths despite having
“old” patients. “Their average age is nearly
55 years,” he said. “They are no longer very active
members of society.” This comment is strange to
modern ears, but the average life span at the time
was 47 years. For fear of spreading cancer with a
biopsy, diagnosis was almost always clinical, estab-
lished histologically after the operation. In doubtful
cases Halsted said, “The excision of a specimen for

Figure 1–5. William S. Halsted’s radical mastectomy. A case pic-
tured in 1912. The operation resulted in a large wound closed with
skin grafts. Reproduced with permission from the Classics of
surgery library. Surgical papers. William Stewart Halsted. Vol. 2.
Special Edition. Birmingham (AB): L. B. Adams Jr. 1984; Figure 2,
Plate LX. p. 82.

History of Breast Cancer 9

macroscopic or microscopic is never resorted to
except just before operation.”24

Radical surgery had intellectual support from
W.S. Handley’s theory of permeation, which held
that breast cancer spread centrifugally in continuity,
and lymph nodes provided mechanical barriers.
Blood vascular spread was insignificant; tumor
emboli were destroyed by clot.25 Halsted’s operation
was used, with mixed results, for the next 80 years.

Cushman D. Haagensen (d 1990) was both a
staunch supporter and a critic of radical mastectomy.19

His book Diseases of the Breast, published in 1956, is
a classic. Haagensen’s careful analysis of cases treated
at Presbyterian Hospital in New York City resulted in
eight “criteria of inoperability” to discourage inappro-
priate use of the operation. He also standardized phys-
ical breast examination and originated the Columbia
Clinical Classification (CCC) staging system. After
the CCC, staging systems became increasingly sophis-
ticated and eventuated in the current Tumor, Node,
Metastasis system initially adopted in 1954 by the
International Union Against Cancer. Prior to random-
ized clinical trials, staging provided the principal
means for comparing different methods of treatment.

As the nineteenth century came to a close, mas-
tectomy appeared better than no treatment but still
cured less often than not. The actuarial survival of
Halsted’s first fifty cases 5 years from the first
symptom (40.4%) was greater than twice that of
untreated patients in the Middlesex Hospital Charity
Ward in London admitted between 1805 and 1933,
which was 18%.26,27

Two events of this time were momentous for the
future treatment of breast cancer. The first was the
discovery of x-rays, and the second was the discov-
ery that breast cancer was hormone dependent. Dis-
covery of x-rays by Wilhelm Conrad Röntgen in
Würzburg in 1895 provided the basis for radiother-
apy and mammography. The mysterious ray, desig-
nated “x,” not only penetrated tissues but also killed
cancers. One year after Röntgen’s discovery, x-rays
were used to treat three cases of breast cancer, two
by Hermann Goeht in Hamburg and one by Emile
Herman Grubbé in Chicago.4 All three had
advanced, inoperable cancers and died shortly after-
wards. With the development of dosimetry, improve-
ments in instrumentation and appropriate safe-

guards, radiation therapy became an effective local
treatment of inoperable cancers, and a postoperative
(and sometimes preoperative) supplement to mas-
tectomy that ultimately enabled breast-conserving
surgery. The discovery of radium in 1898 by Pierre
and Marie Curie added interstitial radiation to thera-
peutic options. Geoffrey Langdon Keynes in Lon-
don (1932) used radium as the sole treatment of
operable cases.28 The obvious benefit of ionizing
irradiation was in reducing the bulk of large cancers
and in reducing recurrence in treated fields. An
inferred influence on survival proved elusive.

The hormonal treatment of breast cancer began
with oophorectomy. In 1899 Albert Schinzinger
(1827–1911) in Freiburg commented on the poor
prognosis of young women with breast cancer and
proposed castration to age them and slow down the
malignant growth. Independent of this suggestion,
George Thomas Beatson (1848–1933) of Glasgow
performed the first castration for breast cancer
7 years later. Beatson knew by his studies of lactation
that castration or rebreeding of cows shortly after
they calved prolonged milk production, both mea-
sures having in common the interruption of ovarian
function. Since the hyperplastic cells of lactation
decomposed into milk, he reasoned that castration
might make the hyperplastic cells of breast malig-
nancy do so as well. The reasoning was wrong, but
the result was gratifying. In 1896 he reported tempo-
rary tumor regression after oophorectomy in three
cases of advanced breast cancer. Beatson’s discovery
established the palliative value of oophorectomy, and
for a period it became a regular adjuvant to mastec-
tomy by some surgeons.29 Secondary endocrine
surgery with adrenalectomy and hypophysectomy
developed as sequels to oophorectomy, but in time
endocrine surgery was replaced by hormone therapy
(Henry Starling described hormones in 1905) and,
ultimately, by pharmacologic methods of reducing
estrogen production or its effects with luteinizing
hormone-releasing hormone agonists, estrogen
receptor modulators and aromatase inhibitors. Dis-
covery of intracellular estrogen receptors (ER) in
breast cancers by Elwood Jensen in Chicago in 1967
was another milestone in hormone therapy, permit-
ting patients who could benefit from hormone ther-
apy to be distinguished from those who could not.30

10 BREAST CANCER

TWENTIETH CENTURY

The next 100 years resulted in a retreat from radical
surgery and the introduction of mammography and
chemotherapy. Research confirmed a hereditary
component of breast cancer. As important as all else
came a demand for scientific evidence to support
claims of efficacy and to supplant the anecdotes and
polemics of the past. Cooperative groups of clini-
cian investigators amassed large numbers of patients
for study, and randomized, controlled clinical trials
with sophisticated statistical analysis of data became
commonplace. Breast cancer was recognized as a
major health problem in the Western world, stimu-
lating a concerted effort against it.

In the early decades, many sought to improve the
results of radical surgery with “extended” radical
mastectomies. Margottini and Veronesi in Milan,
Caseres in Peru, and Urban and Sugarbaker in the
United States removed the internal mammary nodes.
Dahl-Iverson in Copenhagen removed the supra-
clavicular and internal mammary nodes and Wan-
genstein in Minnesota added removal of mediastinal
nodes. Other than showing that extra-axillary nodes
often contained metastases and that their removal
improved regional tumor control, cures were not
increased, and these extensions were eventually
abandoned in favor of chest wall and regional irradi-
ation. As Handley’s permeation theory lost cre-
dence, D. H. Patey and R. S. Handley in London felt
justified in preserving the pectoralis major muscle
unless it was directly involved by cancer, an opera-
tion they called the “conservative” radical mastec-
tomy. With the support of surgeons in the United
States such as Hugh Auchincloss Jr. in New York,
this operation eventually prevailed in 1979 as the
“modified” radical mastectomy.31

Mammography, unarguably the most important
advance to date in the detection of breast cancer,
developed in parallel with surgery. Even early physi-
cians had recognized that small breast cancers were
the most curable. Mammography allowed many
breast cancers to be detected when clinically occult,
including ductal carcinoma in situ, which was regu-
larly curable. Film-screen mammography involved
penetrating the breast with x-rays to activate a rare
earth screen that glowed in response. This screen

exposed a transparent, photosensitive film in the
same cassette which, when developed, provided an
image in various shades of gray for interpretation. In
Robert Egan’s History of Mammography, he gives
Stafford L. Warren at Rochester Memorial Hospital
in Rochester, New York, credit for early explorations
of mammography beginning in 1926 but also men-
tioned that the German surgeon, Albert Salomon,
performed studies with radiographs of breasts
resected for carcinoma as early as 1913 before his
work was apparently interrupted by World War I.32

The technique met resistance despite such advocates
as Jacob Gershon-Cohen in Philadelphia and
Charles M. Gros in Strasbourg until Egan, while a
radiologist at M. D. Anderson Hospital in Houston,
Texas, developed the soft tissue technique that
allowed mammography to move forward.

An early randomized trial of screening with
mammography and physical examination in New
York by Sam Shapiro and Philip Strax in 1963
demonstrated that 30% of cancers could be detected
by mammography alone, and deaths from cancers
among screened women were reduced 30% com-
pared with unscreened. After a host of radiologists
was trained in the technique of mammography, a
demonstration project, the Breast Cancer Detection
Demonstration Project (BCDDP), begun in 1973
and sponsored by the National Cancer Institute and
the American Cancer Society (ACS), screened
283,222 asymptomatic women. The BCDDP estab-
lished the feasibility of mass population screening.
Multiple randomized clinical trials of screening fol-
lowed, showing that regular mammograms could
detect 85 to 90% of asymptomatic breast cancers
with a reduction of breast cancer mortality. Periodic
mammograms and physical examinations for detec-
tion of breast cancer in asymptomatic women 40
years of age and older received endorsement by the
NCI, ACS, and numerous professional groups.33

Mammography was followed by a number of
innovative means for imaging the breast. Xeromam-
mography appeared briefly.34 This dry-process tech-
nique recorded all structures in the breast with
equally good detail and could be examined without
view boxes, but it disappeared from use after further
improvements in film-screen mammography. Endur-
ing adjuncts to mammography were ultrasonography

History of Breast Cancer 11

and magnetic resonance imaging (MRI). Ultrasonog-
raphy came into use in the 1950s. As well as allow-
ing for the distinction between cysts and solid
masses, it could characterize solid masses and per-
mitted irradiation-free, real-time, guided needle
biopsy of suspicious lesions. Malignant lesions
detected by other means were not always visible on
ultrasonography, and results were highly operator-
dependent, making it unsuited for population screen-
ing. MRI proved valuable in special situations.

As the twentieth century advanced, opposition to
radical surgery grew. Kaae and Johansen in Denmark
and Robert McWhirter in Scotland maintained that
simple mastectomy with regional irradiation was the
equal of radical mastectomy, and preferable.35

McWhirter protested that the selective use of radical
mastectomy made the results look better but offered
no overall increase in cures. George Crile Jr. in
Cleveland argued for conservative surgical treatment
based on a biological view of breast cancer, largely
immunologic.36 Most compelling, however, was that
radical surgical removal of tissues had reached its
limits with no decrease in mortality rates. In 1939
Gray showed that early lymphatic spread to axillary
nodes was by embolism rather than by permeation,
and blood vascular spread was increasingly accepted
as the mechanism of general dissemination.37,38

Bernard Fisher, Professor of Surgery at the Uni-
versity of Pittsburgh and a researcher in the biology of

metastasis, became the intellectual leader and the
most compelling spokesman for the need to critically
re-evaluate the treatment of breast cancer. Fisher’s
laboratory investigations indicated that lymph nodes
were not effective barriers to cancer spread. Referring
to Halsted’s rationale for radical mastectomy, Fisher
wrote in 1970 that, “…either the original surgical
principles have become anachronistic or, if they are
still valid, they were conceived originally for the
wrong reasons.”39 Much like a modern Galen, Fisher
asserted that breast cancer was a systemic disease and
that its course was determined by a biologic struggle
between tumor and host. Fisher implied that viable
cancer cells always, or almost always, disseminated
before diagnosis. His thesis presented two testable
hypotheses: (1) variations in local treatment were
unlikely to influence cure, and (2) effective systemic
treatment was necessary to improve cure rates. As
Chairman of the National Surgical Adjuvant Breast
and Bowel Project (NSABP), Fisher was able to
implement large, randomized, controlled clinical tri-
als to test these concepts and to stimulate others to do
the same (Figure 1–6). The results confirmed the
observations of Moore, Küster, and Halsted, namely,
that limited operations resulted in poor local and
regional control, and that patients with recurrence
fared poorly.40–42 As predicted, they also confirmed
that whether the regional nodes or the whole breast
were removed, overall cure rates among different

Figure 1–6. Bernard Fisher MD, modern researcher in the biology of breast cancer who revised Halstedian concepts, (fourth from the right
in the front row) with early members of the NSABP at a group meeting in Florida, May 1978.

12 BREAST CANCER

treatment groups proved similar. The explanation
offered was that failure of local control indicated
incurability at the outset. But the need to retreat (“sal-
vage”) was distressing for all, and as local or regional
recurrence might jeopardize cure for some, optimum
tumor control at the outset remained a priority.

The greatest impact of these trials was on man-
agement of the breast itself. As confidence grew in
irradiation for controlling occult regional metas-
tases, the question was whether irradiation could do
the same for occult tumor in the breast. Selected
cases so treated by F. Baclesse in France, Ruth
Guttman in the United States, Sakan Mustakallio in
Finland, and others had suggested this was the case
as early as 1965.43 After an initial but unsatisfactory
beginning at Guy’s Hospital in London, controlled
trials of breast conservation started in Milan, Italy,
in 1973 by Umberto Veronesi and by the NSABP in
1976.44,45 These trials established that excision of the
primary tumor, “lumpectomy,” followed by whole
breast irradiation was as effective as total mastec-
tomy for both local and ultimate disease control of
most early-stage cases and was an obvious cosmetic
improvement. Based on these outcomes, in 1990 the
NCI sanctioned breast-conserving surgery as the
preferred treatment of stage I and II breast cancers.46

Axillary sentinel lymph node biopsy (SLNB)
was rapidly adopted after it was introduced in 1997,
making routine axillary lymph node dissection
unnecessary. Axillary dissection could be reserved
instead for cases in which the SLNB showed nodal
metastases, thereby sparing many the morbidity of
this operation.47 Surgical treatment of the breast and
the regional nodes could be customized to individual
needs, and with the combination of SLNB and
breast conservation, the surgical component of mul-
tidisciplinary treatment reached a minimum.

Chemotherapy developed in parallel with changes
in local treatment. Its beginnings can be traced to the
use of mustard gas in World War I. Exposure caused
depression of bone marrow and lymphoid tissue fol-
lowed by death from pneumonia. The effects on tis-
sues were similar to those of ionizing radiation and
suggested usefulness against lymphomas. Experi-
ments with animals followed, and, indeed, nitrogen
mustard produced regression of implanted lymphoma
in mice. In 1942 it was first used to treat human lym-
phoma at Yale University; the results of which were

not reported by Goodman and Philips until 1946, a
delay necessitated by the need for wartime secrecy.
Reference is sometimes made in texts to events sur-
rounding explosion of mustard agent (dichloroethyl
sulfide) bombs aboard the S.S. John Harvey on
December 2, 1943, in Bari Harbor, Italy, during WW
II as the stimulus for research into chemotherapy, but
this event followed the clinical investigations at Yale
University.48 Continued development produced such
therapeutically useful alkylating agents as busulfan,
cyclophosphamide and chlorambucil. Additional
agents with various mechanisms of cytotoxicity fol-
lowed. None proved toxic specifically for cancer cells
or free of undesirable side effects, and none cured
overt breast cancers, but their judicious use proved
clinically useful. Systemic “chemotherapy,” a word
coined by the researcher Paul Erlich, often produced
temporary regression and occasionally complete dis-
appearance of advanced breast cancers.49 Initial trials
of intravenous, perioperative triethlylene-thiophos-
phoramide (Thio-TEPA) in the late 1950s, intended to
destroy tumor cells released during mastectomy, were
failures, but extended adjuvant treatment with
L-phenylalanine mustard directed against occult
micrometastases improved the survival of patients
with early stage breast cancer.50,51 A similar approach
using combinations of drugs with different mecha-
nisms of action (eg, cyclophosphamide, fluorouracil,
and methotrexate (CMF), and doxorubicin combina-
tions) proved more effective, securing adjuvant
chemotherapy an established place in multidiscipli-
nary treatment. With the addition of chemotherapy,
treatment of breast cancer truly became a coordi-
nated effort of specialists, bringing to bear a medley
of surgery, radiation therapy, and systemic chemo-
hormonal therapy on the local and systemic compo-
nents of the disease.

As the twentieth century closed, breast cancer was
recognized as a disorder of unrestrained cell growth,
but its instigation remained an enigma. A virus caused
the disease in mice, but apparently not in humans;
ingestion of aromatic hydrocarbons (dimethylbenzan-
thracene) produced it in rats. In humans, exposure to
ionizing radiation increased risk, as evidenced in sur-
vivors of the atomic bombing of Hiroshima during
WW II and the recipients of multiple fluoroscopies
incident to treatment of pulmonary tuberculosis, infor-
mation spurring closer regulation of mammography

History of Breast Cancer 13

and other radiological procedures. Hormone replace-
ment therapy to alleviate menopausal symptoms also
increased risk, prompting cautions about exposure to
exogenous estrogens.52 The discovery of predisposing
mutations in BRCA1 and BRCA2 genes of families
prone to breast cancer confirmed genetic transmis-
sion and provided a means to identify individuals at
great risk.53,54 Among preventive strategies, early cas-
tration was effective but unacceptable; in 1998
tamoxifen, a synthetic estrogen receptor modulator,
became the first drug proven to lower risk and the
first approved for this use.55 Prophylactic mastec-
tomies offered almost total protection, and became an
option for women especially in need.56

Breast cancer remained a daunting problem as
science and medicine reached the third millennium
AD, but a problem more accurately defined than ever
before and upon which all the tools of modern science
were brought to bear. Research explored cellular
growth factors and intracellular signaling pathways
that might be exploited against it. For practicing
physicians radiotherapy, medical oncology, surgical
oncology, and even breast surgery had become spe-
cialties. Cancer institutes dotted the country. For the
record, in the United States in 2004 an estimated
217,000 women continued to develop breast cancer
each year and 40,000 died of it annually. With screen-
ing and modern therapy, the death rate had begun to
decline and overall relative survival 5 years after diag-
nosis, cured and uncured, was 86.6%.57

COMMENT

The sometimes heroic, often tragic, and always
poignant story of breast cancer is incomplete; happy
will be the day when the final chapter is written.
When that day comes, it may not get the attention it
deserves. It will come in familiar voices on the
nightly news: “Today doctors at (some) medical cen-
ter announced that a (vaccine?) prepared from the
(prions?) of breast cancer resulted in immediate and
total disappearance of all signs of the disease in
eleven advanced cases. Further studies are planned
to follow up this promising development. In interna-
tional news…” Reactions will be mixed. Most will
notice without comment. Skeptics will quip, “Yeah,
another breakthrough!” But it will be true. Others,
robbed of loved ones, will hesitate in melancholy

reflection. More than suspected will reap the
rewards, and after more than 5,000 years of telling,
the story of breast cancer will have been told.

ACKNOWLEDGMENT

The author wishes to thank Judith H. Donegan, MD,
PhD, for constructive criticism of the manuscript.

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BREAST CANCER
• Copyright
• Dedication
• Contents
• Preface
• Contributors
• Ch01: History of Breast Cancer
• Ch02: Anatomy of the Breast, Axilla, and Thoracic Wall
• Ch03: The Evolving Concept of the Breast Cancer
• Ch04: Epidemiology of Breast Cancer
• Ch05: Genetics, Natural History, and DNA-Based Genetic Counseling in Hereditary Breast Cancer
• Ch06: Molecular Basis of Breast Cancer
• Ch07: Breast Cancer Risk Assessment and Management
• Ch08: Role of Screening in Breast Cancer Mortality Reduction
• Ch09: Diagnostic Breast Imaging
• Ch10: Sonography of Breast Cancer
• Ch11: Magnetic Resonance Imaging
• Ch12: Diagnostic Techniques
• Ch13: Pathology of Invasive Breast Cancer
• Ch14: Staging and Histologic Grading
• Ch15: Ductal Carcinoma In Situ
• Ch16: Oncoplastic Surgery of the Breast
• Ch17: Evaluation and Surgical Management of Stage I and II Breast Cancer
• Ch18: Locally Advanced Breast Cancer
• Ch19: Axillary Staging and Therapeutics
• Ch20: Adjuvant Chemotherapy
• Ch21: Endocrine Therapy of Early and Advanced Breast Cancer
• Ch22: Radiation Therapy in Early and Advanced Breast Cancer
• Ch23: Evolution in Breast Reconstruction
• Ch24: Unusual Breast Histology
• Ch25: Multifocal, Multicentric, and Bilateral Breast Cancer
• Ch26: Breast Cancer in the Previously Augmented Breast
• Ch27: Breast Cancer in the Irradiated Breast
• Ch28: Novel Radiation Therapy Techniques
• Ch29: Novel Radiation Therapy Techniques
• Ch30: Hormone Therapy and Breast Cancer
• Ch31: Male Breast Cancer
• Ch32: Management of Locoregional Recurrences
• Ch33: Breast Cancer and Multiethnic/Multiracial Populations
• Ch34: Image-Guided Ablation for Breast Cancer
• Ch35: Lymphedema
• Ch36: Surveillance Strategies for Breast Cancer Survivors
• Ch37: A Patient’s Perspective
• Index
• Exit

1

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Published: 08/06/2017 Received: 20/03/2017

ecancer 2017, 11:746 https://doi.org/10.3332/ecancer.2017.746

Copyright: © the authors; licensee ecancermedicalscience. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction
in any medium, provided the original work is properly cited.

The past and future of breast cancer treatment—from the papyrus to
individualised treatment approaches
Felipe Ades1, Konstantinos Tryfonidis2 and Dimitrios Zardavas3

1Hospital Albert Einstein, Avenida Albert Einstein, 627 – Morumbi, São Paulo – SP, 05652-900 Brazil
2European Organisation for Research and Treatment of Cancer, Avenue E. Mounier 83/11, 1200 Brussels, Belgium
3Breast International Group (BIG), Boulevard de Waterloo 76, Brussels 1000, Belgium

Correspondence to: Felipe Ades. Email: felipeades@gmail.com and felipe.ades@einstein.br

Abstract

Cancer is one of the oldest diseases ever described, since ancient Egypt there have always been attempts to treat and cure this illness.
The growing body of knowledge about breast cancer biology and improvements in surgical and medical treatments has been built over time
with contributions from many talented and enthusiastic physicians and researchers. Medical advances have changed the approach from a
previously incurable condition, into a surgical disease. Further improvements in cancer biology have allowed the development of systemic
treatments, hormonal therapies, and targeted drugs. The description of the molecular intrinsic subtypes of breast cancer clarified the under-
standing of breast cancer as a group of heterogeneous diseases, associated with different clinical outcomes, and therapeutic opportunities.
This paper reviews how breast cancer treatment has improved since the earliest descriptions, in ancient times, and how future approaches,
such as gene signatures, molecular profiling, and liquid biopsies, aim to further develop individualised treatments and improve treatment
outcomes.

Keywords: breast cancer, cancer history, breast surgery, gene signature, molecular profiling, liquid biopsy

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Breast cancer treatment in ancient times

Cancer is one of the oldest diseases ever described by medicine. One of the earliest manuscripts reporting on cancer treatment was the
Egyptian papyrus of Edwin Smith, dated 1600BC but possibly a copy from a much older document, from 2500 to 3000BC [1]. It is consid-
ered to be the first known medical treatise, as it embraces a rational and scientific approach towards medical treatments, in contrast with
older manuscripts that reported magic and other mystical methods to treat diseases. The papyrus describes 48 generic clinical cases where
rudimentary surgical procedures were used to treat wounds, fractures, and cancer, according to the different parts of the body. The part
dedicated to the breast depicts techniques to treat breast cancer and wounds, but not with the objective to eradicate with curative intent,
as cancer, at that time, was considered an incurable illness [2].

Around the year 400BC, the Greek physician Hyppocrates, considered the ‘father of medicine’, created the term cancer. The name derived
from the word ‘karkinos’, which is the Greek term for crab or crayfish, in an analogy for the invasive behaviour of the disease, touching and
invading nearby tissues [3]. Others believe that the analogy was due to the similarities between the vascularisation of the tumour and the
crayfish’s legs. In the second century, the also Greek doctor Galen created the term oncos (the Greek work for swelling) to refer to malig-
nant diseases. Galen believed that diseases were caused by an imbalance of humours and breast cancer had a systemic nature due to the
accumulation of black bile in the blood [4].

From the middle ages to the present day

With the ascension of the monotheistic religions, little progress in medicine was made in Europe. Early Christian views attributed the cause
of diseases to God, and treatments, likewise, were based on faith and miracles rather than on surgery and medications. Only in the 10th
century, with the rise of the Islamic empire, was Greek medicine revived and expanded due to the work of physicians like Ibn Sina [5] and
Abu Al-Qasim Al-Zahrawi (aka Albucasis) [6]. Accurate translations of the medical manuscripts and the establishment of the early medical
schools allowed the continuation of medical development [7]. However, the dissection and representation of the human body remained
forbidden by religious traditions, limiting additional expansion of medical knowledge [8].

Albucasis, along with the French surgeons Henri de Mondeville [9] and Guy de Chayliac [10], added unique instruments to the surgical
procedures to remove breast tumours. But it was not until the 16th century that breast surgery flourished. The improvement of surgical
and medical sciences occurred in the context of the age of enlightenment. Detailed anatomical descriptions made by Adreas Versalius,
Leonardo da Vinci and others paved the road to a better understanding of the human body allowing the advance of surgical techniques
[8]. In Scotland, the surgeon John Hunter [11] established the initial concept of staging; ‘if the tumour is moveable, there is no impropriety
in removing it’ [12]. Nevertheless, surgical approaches were limited due to technology issues; until the mid-19th century, anaesthesia was
not yet developed for surgical procedures [13]. Surgeons had to rely on technique and, mostly, speed to perform tumour resections. In
parallel, investigations on a wide range of carcinogens suspected to be involved in breast cancer development and progression started to
be conducted [7]. For the first time, medicine aimed to cure breast cancer.

19th century—the beginning of modern breast cancer treatment

The 19th century saw great improvements in the understanding of the disease and its mechanisms. Observations made by Virchow [14]
and others underpinned the cellular nature of cancer cells and its differences from their healthy counterparts. This observation dismissed
many of the previous humoural theories as causes of cancer and its metastasis. Metastatic spread was due to the dissemination of these
cells by the lymphatic and blood vessels.

A range of new surgical approaches were developed given the growing body of information on carcinogenesis and metastasis mechanisms
and important improvements were made on surgical techniques, such as anaesthesia, surgical gloves and vestments, and disinfection.

In particular, anaesthesia [13] and disinfection allowed, for the first time, surgical freedom to perform wider resections. The en bloc resec-
tion was experimented by a range of skilled surgeons such as Charles Moore [15], in the United Kingdom, and Kuster and Volkmann [16],

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in Germany. Axillary dissection was used as part of the surgical treatment of breast cancer by Banks in Liverpool [17]. In 1894, the surgeon
William Halsted [18] described the surgery that became the standard of care for many years to come, the radical Halsted mastectomy.
Believing that the disease had an initial local behaviour with a constant path of dissemination, from the breast to the axillary nodes, and
only then to distant locations of the body, Halsted developed a technique that would remove the whole tumour in one piece along with the
pectoral muscles, lymphatic vessels, and the axillary lymph nodes [18]. The one piece removal would avoid unattended cancerous tissues
being left behind and no lymphatic vessels would be damaged, thus no contamination of healthy tissue by cancer cells would occur [19].
Despite the radical approach and the profound side effects of this wide procedure, this was the first time in history that breast cancer could
be systematically and scientifically cured.

Modern times—more improvements and fewer morbidities

In the 20th century, a rapid expansion in medical knowledge was made, with advances seen in multiple areas of medicine. As with surgery,
improvements in radiotherapy, chemotherapy, and endocrine therapy were preceded by an accumulation of knowledge about the patho-
logic mechanisms of the disease.

The surgeon Thomas Beatson, experimenting with animal models, observed that breast tumours in these animals regressed after oopho-
rectomy [20]. The relation of sexual hormones with breast cancer was only elucidated later, in 1967, when Elwood Jensen described the
oestrogen receptor, paving the road for the development of a range of oestrogen-modulating drugs [21].

The development of chemotherapy also happened in the second half of the 20th century; first with the mustard gas derivatives [22], followed
by a rapid expansion in the chemotherapy portfolio after the heavy financing of cancer drug research established by the US National Can-
cer Act of 1971 [23]. The pivotal work of the oncologists Bernard Fisher [24], in the USA, and Gianni Bonadonna [25], in Italy, investigated
the role of cytotoxic drugs in improving breast cancer cure, inaugurating the concept of adjuvant treatment. In 1975, Gianni Bonadonna
presented the first report on the efficacy of cyclophosphamide, methotrexate, and fluorouracil (CMF) as adjuvant treatment. These results,
along with those reported by Dr Fisher´s National Surgical Adjuvant Breast and Bowel Project, raised hopes that chemotherapy could
have a major role in the management of breast cancer, and were of seminal importance for all the studies on adjuvant systemic therapy
conducted throughout the world [26]. Since then, breast cancer chemotherapy schedules improved from the methotrexate combinations,
to anthracyclines and the incorporation of taxanes in the 1990s [27].

Taking advantage of the available new therapeutic options, visionary physicians started to combine treatment modalities, improving results,
and reducing morbidities. One of the most preeminent surgeons leading this shift in breast cancer treatment was Umberto Veronesi. Work-
ing with the oncologist Gianni Bonadonna, at the Istituto Nazionale Tumori, in Milan, the Italian team aimed to perform partial breast surger-
ies followed by radiotherapy, chemotherapy, and tamoxifen, when applicable. The concept of sentinel lymph node dissection to avoid full
axillary dissection was also investigated in this context. This less aggressive approach was proved to be as effective as the more radical
and mutilating Halsted method [28]. Tailoring the surgery method and the adjuvant treatment according to each patient started to be a real-
ity. The era of personalised therapy was inaugurated.

Molecular era of cancer treatment

The proof of concept demonstrated by treatment tailoring according to each patient’s characteristics, staging, and molecular profile was a
watershed in cancer treatment and research. Advances achieved in breast cancer treatment served as models to improvements in many
other areas of oncology.

Conventional histological evaluation of breast cancer by pathologists has identified several histological subtypes; however, this morphol-
ogy-based breast cancer taxonomy is of limited relevance in terms of tailoring treatment strategies for individual patients. More than 15
years ago, the employment of the back then newly developed microarrays and the gene expression profiling analysis techniques resulted in
the identification of the so-called breast cancer intrinsic subtypes [29, 30]. This proved to be a major conceptual breakthrough, since it iden-
tified different molecular subtypes of breast cancer with distinct clinical behaviour and therapeutic vulnerabilities that can be summarised

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as follows: (i) luminal A breast cancer with expression profile reminiscent of luminal lineage mammary cells, with indolent clinical behaviour,
heightened ER-signalling pathways activation and sensitivity to endocrine treatment, (ii) luminal B breast cancer showing poorer prognosis
as compared to their luminal A counterparts and higher proliferation status coupled with reduced endocrine sensitivity [31], (iii) HER2-like,
associated with HER2/ErbB2 gene amplification, and (iv) basal-like breast cancer, associated with strong basal epithelial marker expres-
sion, as well as hormone receptor negativity, high proliferation levels and reduced luminal epithelial and cytokeratin expression [29].

Treatment and clinical research started to rely not only on morphologic and clinical–pathologic features but on cellular behaviour. Deeper
understanding of the cellular and molecular biology of breast cancer allowed the detection of genetic aberrations possibly targetable by
new compounds [32].

Breast cancer treatment, what next?

Breast cancer treatment, as it stands today, is selected according to the ‘group of patients’ a specific individual ‘fits in’. As has happened in the
past, we are coming to a moment where different approaches to breast cancer treatment need to be developed. Selecting treatments according
to the results of the clinical and available molecular tests, indeed, enriches the chance of response to a given treatment strategy, by classifying
the patient to a specific subgroup. Nevertheless, individual characteristics that could play a role in the selected patient remain an open area of
research. Understanding the individual molecular patterns and aberrations of each patient is an approach that could change today’s ‘stratified’
treatment, based on the intrinsic subtype groups, to a really individualised treatment, based on patients’ specific molecular characteristic.

The open question is how we take the heritage of knowledge produced by our professors from the past and move on to another level,
towards really personalised medicine?

Molecular dissection of breast cancer: intrinsic subtypes and beyond

During recent years, there has been increasing reference to so-called personalised cancer medicine, defined as: ‘A form of medicine that
uses information about a person’s genes, proteins, and environment to prevent, diagnose, and treat disease. In cancer, personalised medi-
cine uses specific information about a person’s tumour to help diagnose, plan treatment, find out how well treatment is working, or make
a prognosis’ [33]. Personalised medicine has been alternatively described by the term ‘precision medicine’ and it represents an effort to
individualise the clinical practice applied to any given patient [34].

In the field of breast cancer, there was an early implementation of some of the above-mentioned principles of personalised cancer medicine,
namely through the therapeutic targeting of hormone receptor signalling [35]. The successful clinical development of tamoxifen for patients
with hormone receptor-positive breast cancer represents the archetype of personalised medicine applied in oncology [36]. Subsequently,
the development of trastuzumab, the first-in-class HER2-blocking agent, for patients with HER2-positive disease exemplified further the
improved clinical outcomes that personalised cancer medicine can achieve [37]. Of note, in both cases, a true personalisation is yet to be
achieved; it is more accurate to refer to stratified cancer medicine, given that for individual patients with hormone receptor positive or HER2-
positive breast cancer treated with endocrine treatment or HER2 blockade, respectively, therapeutic resistance can occur. This indicates
that further refinement of triaging patients with the respective treatment is needed, for implementing truly personalised cancer medicine.

The introduction of the intrinsic subtypes of breast cancer, maybe more than anything else, contributed to the dissemination of a conceptual
advance; that of breast cancer being a group of heterogeneous diseases, associated with different clinical outcomes and therapeutic oppor-
tunities, as will be detailed later. Both aspects have been capitalised ever since to achieve improved patient stratification in terms of accu-
rate prognostication and treatment decisions, bringing us several steps closer to the realisation of personalised breast cancer medicine.

The distinct nature of the breast cancer intrinsic subtypes has been reinforced by studies that coupled gene expression-profiling analysis
with gene copy number analysis, indicating that the former ones are associated with recurrent copy number aberrations (CNA). More
recently, the introduction of powerful next-generation sequencing (NGS), also known as massively parallel sequencing, enabled an unprec-
edentedly detailed characterisation of the molecular underpinnings of breast cancer. Several studies applied this high-throughput molecular
analysis method to collections of primary breast tumour samples, identifying recurrent gene mutations and/or CNAs among the different
intrinsic subtypes; some of them are currently pursued as potential therapeutic targets (Table 1) [38, 39].

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Table 1. Summary of main characteristics of the intrinsic subtypes of breast cancer.
Luminal A Luminal B HER2-enriched Basal like

IHC Surrogate ER(+) and/or PR(+),
HER2(−), Ki67 < 14% (St Gallen)

ER(+) and/or PR(+),
HER2(−), Ki67 ≥ 14%
(St Gallen)

ER(±), PR(±), HER2(+)
(St Gallen)

ER(−), PR(−), HER2(−)
(St Gallen)

Prognosis Good Intermediate Poor Poor
Treatment vulnerability Endocrine treatment Endocrine treatment +

Cytotoxic chemotherapy
HER2 blockade Cytotoxic chemotherapy

Recurrent CNAs:
Increased copy number

Decreased copy number

High-level amplification

1q, 16p

16q

8p11-12,
11q13-14,
12q13-14,
17q11-12,
17q21-24,
20q13

1q, 8q, 17q, 20q

1p, 8p, 13q, 16q, 17p,
22q

8p11-12, 8q, 11q13-14

1q, 7p, 8q, 16p, 20q

1p, 8p, 13q, 18q

17q

3q, 8q, 10p

3p, 4p, 4q, 5q, 12q, 13q,
14q, 15q

Rare

Recurrent gene
mutations (Top-5)

PIK3CA (45%)
GATA3 (14%)
MAP3K1 (13%)
TP53 (12%)
CDH1 (9%)

TP53 (29%)
PIK3CA (29%)
GATA3 (15%)
MLL3 (6%)
MAP3K1 (5%)

TP53 (72%)
PIK3CA (39%)
MLL3 (7%)
AFF2 (5%)
PTPN22 (5%)

TP53 (80%)
PIK3CA (9%)
MLL3 (5%)
RB1 (4%)
AFF2 (4%)

Improving prognostication of patients with early-stage breast cancer

The advent of microarrays contributed to more accurate breast cancer patient stratification, not only through the identification of the afore-
mentioned intrinsic subtypes, but also through the development of the so-called first-generation prognostic gene signatures. These multigene
prognosticators have been developed through the assessment of the epithelial compartment of primary breast tumours. Currently, several of
these first-generation prognostic gene signatures are clinically available: (i) Endopredict (Sividon Diagnostics, Cologne, Germany) (ii) Mam-
maPrint (Agendia, Amsterdam, the Netherlands), (iii) MapQuant DX (Ispogen, Marseille, France), (iv) Oncotype DX (Genomic Health, CA,
USA), (v) PAM50 (Nanostring Technologies, WA, USA), (vi) Theros (bioTheranostics, CA, USA), (v) (Table 2). The importance of such multi-
gene prognostic data is emphasised in the newest AJCC breast cancer staging system 2017 update. In this update, when molecular data is
available, it can influence the prognostic classification of the disease, providing additional information to the traditional TNM evaluation [40].

It should be noted that the above mentioned first-generation prognostic gene signatures can refine the prognostication of patients with
hormone receptor positive early-stage breast cancer, but not other subtypes of the disease; indeed, the two fundamental biological
phenomena assessed through them are ER signalling and proliferation status. Furthermore, they disregard the stromal compartment of
the disease, for which there is increasing evidence supporting its functional importance for malignant progression through interactions
between cancer and stromal/immune cells [41, 42]. Consecutively, there has been a second wave of efforts trying to further refine the
prognostication of patients with operable breast cancer, assessing the functionally important stromal component of the disease, as well
as the differences among the distinct molecular subtypes.

This has been exemplified by the development of a stroma-derived prognostic predictor (SDPP), a 26-gene prognosticator that was devel-
oped through an assessment of tumour stroma [43]. Another example of a second-generation prognostic gene signature was developed
through a comparison of CD10+ cells from cancerous and normal mammary tissues, leading to a 12-gene prognostic signature [44].
Regarding triple-negative breast cancer, there have been initial efforts to generate immune-related prognostic signatures with promising
results [45, 46]. More recently, a study mining data from The Cancer Genome Atlas reported two immune/inflammatory gene signatures,
one associated with poor and one with favourable prognosis among patients with basal-like breast cancer [47].

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Table 2. Summary of commercially available, first-generation, multigene prognosticators in breast cancer.

Endopredict MammaPrint MapQuant DX Oncotype DX PAM50 Theros
Number of Genes
assessed

8 70 97 21 50 2

Types of tumour
material

Fresh-frozen FFPE Fresh-frozen FFPE FFPE FFPE

Technique qRT-PCR DNA microarrays DNA microarrays qRT-PCR nCounter qRT-PCR
BC subtype
indication

ER+/HER2-BC
treated with
adjuvant ET

Stage I or II BC,
LN-, T ≤ 5 cm

ER+ Grade 2 BC,
treated with
adjuvant ET

ER+ BC treated
with adjuvant ET

and/or CT

ER+ BC treated
with adjuvant ET

ER+ BC treated
with adjuvant ET

Prospective
clinical evidence

No Yes (MINDACT) No Yes
(TAILORx)

No No

Regulatory
approval

No Yes
(FDA)

No No No No

Company Sividon Diagnostics Agendia Ipsogen Genomic Health Nanostring
Technologies

bioTheranostics

Abbreviations: BC: breast cancer, CT: chemotherapy, ER: oestrogen receptor, ET: endocrine therapy, FDA: food and drug administration, HER2: human
epidermal growth factor receptor 2, LN: lymph node, MINDACT: microarray in node-negative and 1–3 positive lymph node disease may avoid chemotherapy,
qRT-PCR: q-reverse transcription polymerase chain reaction, TAILORx: trial assigning individualised options for treatment (Rx)

It should be noted that there is no prospective evidence for second-generation prognostic gene signatures supporting their implementation
in clinical practice from prospectively conducted randomised studies; thus, their clinical utility still needs to be proven [48]. Truly person-
alised prognostication of patients with early-stage breast cancer is a goal to be further pursued that could be reached through the assess-
ment of plasma-based biomarkers.

Tailoring systemic treatment

There is an increasing evidence that patient-derived tumour xenografts (PDX) models, alternatively termed tumour avatar models, can be
valuable tools promoting cancer translational research and advance personalised cancer medicine [49].

The promise of liquid biopsies

A conceptual breakthrough has been introduced during recent years in the field of oncology, promising to take us several steps closer to truly
personalised cancer medicine: that of liquid biopsies [50]. The following types of molecular entities have been reported as possibly relevant
for oncology: (i) circulating tumour cells (CTCs) that can be assessed at the DNA, RNA and protein level; of note CTCs offer opportunities
for functional assessment, (ii) cell-free DNA (cfDNA), alternatively called circulating tumour DNA (ctDNA), referring to DNA fragments shed
to the circulation by cancer cells, (iii) tumour-educated blood platelets, which have been shown to be subjected to changes at the RNA level
through their interaction with cancer cells [51], and (iv) microvesicles/exosomes, corresponding to extracellular vesicles, carrying protein-
and nucleic acid-content that corresponds to biological messages transmitted from tumour cells to recipient normal cells [52, 53]. To the
present day, CTCs and ctDNA are the most extensively studied types of liquid biopsies that could impact the following aspects of oncology:

A. Cancer screening

In a study of lung cancer-free subject, CTCs were assessed in patients with chronic obstructive pulmonary disease (COPD) and
subjects without this condition but matched for smoking habits [54]. There were five patients with COPD (3%) tested positive for

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CTCs and none from the control group; the annual CT surveillance detected lung parenchyma nodules 1–4 years following the CTCs
detection, resulting in diagnosis of early-stage lung cancer [54]. Such results have not yet been reported for breast cancer; however,
it could be envisioned that early CTCs’ detection could complement breast cancer screening for subjects at high risk. Emerging
powerful technologies of ctDNA detection with increasing sensitivity could be also assessed as potential tools of personalised cancer
screening [55].

B. Monitoring of minimal residual disease

The assessment of minimal residual disease is a well-established clinical practice in the management of patients with leukaemia [56], but
not in solid tumours; therapeutic decisions in the latter ones are taken on the basis of assessment of the primary tumour and there is no
measurable parameter to inform about either response to treatment or occurrence of disease recurrence. The assessment of either ctDNA
or CTCs could be possibly useful for the monitoring of minimal residual disease. In a prospectively conducted study, CTCs were assessed
using the CellSearch® System evaluated patients with operable breast cancer before the onset of adjuvant chemotherapy administration
and after chemotherapy [57]. Prior to adjuvant treatment, 21.5% of the patients were tested positive for CTCs, whereas after chemotherapy
this percentage reached 19.6%; there was no correlation of standard clinico-pathologic risk factors and the detection of CTCs. CTCs
detection was found to be an independent detrimental prognostic factor, indicating that CTCs could be a measurable parameter assessing
minimal residual disease in patients with early-stage breast cancer.

A promising implementation of liquid biopsies would be to guide adjuvant treatment selection and monitor its therapeutic effect; such pre-
liminary results have been generated through the assessment of disseminated tumour cells (DTCs) in the bone marrow of patients with
early breast cancer [58].

C. Guidance of treatment selection

The ultimate breast cancer medicine personalisation would occur through a ‘real-time’ monitoring of treatment activity, as well as a person-
alised treatment selection to target therapeutic vulnerabilities at the individual patient level. Theoretically, liquid biopsies could serve both
purposes. In the classical paradigm, monitoring of treatment activity is performed through conventional image analysis and/or functional
imaging assessments, complemented by clinical examination, in particular for patients with advanced disease; such objective read-outs to
monitor treatment activity are lacking for patients with primary disease. This means practically that a patient must receive several cycles
of treatment prior to the monitoring of the respective effect; for some patients, this means that the futility of a therapeutic strategy will be
identified only retrospectively.

Conclusions

Accumulation of knowledge over time has changed breast cancer from an incurable condition to a range of different diseases with specific
molecular aberrations, clinical behaviours, and patterns of response to systemic treatments. These improvements are a huge achievement
for humanity and have been accomplished over time with the contributions of many bright and passionate individuals. To continue this
legacy, and take it to a new level of excellence, efforts in further understanding breast cancer biology and its interactions with the immune
system and the microenvironment are being conducted. Prognostic and predictive genetic signatures are already a reality in breast can-
cer management and are being further refined. Liquid biopsy strategies are in current use for other indications and in research for breast
cancer, in several settings. Refining our understanding of disease mechanisms and molecular characteristics is key to improving drug
development and treatment approaches.

Disclosures

The authors have declared no conflicts of interest related to the present manuscript.

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De La Cruz 0

Claudia De La Cruz

Donald Moore

ENC 1143

Wednesday, February 17, 2021

A Concise History of Breast Cancer

Over the past half-century, the understanding of breast cancer biology has transformed, showing us improvements in early techniques, is the most frequently diagnosed type of cancer and second leading cause of cancer death in women after lung cancer. Statistics show that breast cancer affects more than 1,000,000 women worldwide each year, and about 450,000 die from the disease. Breast cancer is a very old disease. The story of breast cancer helps to divide it into three predominant eras times where in the guidelines of care were driven generally by ruling a hypothesis. Breast cancer was treated by surgery or traditional medicine, but rarely cure. Cases described as “breast cancer” were in various civilizations, from Ancient Egypt to the Western Middle Ages. Also, other cases such as tumor progression was also mentioned. Breast cancer was among the most widespread cancers. In the 15th century, researchers and surgeons started to better comprehend the human body. Surgery for breast cancer was implemented, but still was a risky operation at that time since operations were long and painful due to lack of anesthesia and antiseptic conditions. Physician Philippus Theopharstus Aurelus Bombastus von Hohenheim (1493-1541), called Paracelsus, meaning “beyond Celsus”, though that cancer was a product of excess or deficiency of certain fluids rather than an imbalance in the body’s humors. He suggest replace Galen’s black bile by”ens” (entities): ens astrorum (cosmic influences differing with climate and country). In this paper, we will briefly explain the history of breast cancer focusing on the discoveries and inventions in the field of breast cancer detection, analysis, and treatment.

Greek and Roman period (460 BC-475 AD)

Prior written history Ancient Greece was know by mythology based on a belief between humans an gods.

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