BBA Clinical 7 (2017) 64–77

Contents lists available at ScienceDirect

BBA Clinical

journal homepage: www.elsevier.com/locate/bbaclin

Understanding breast cancer – The long and winding road

Kiven Erique Lukong
Department of Biochemistry, College of Medicine, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK S7N 5E5, Canada

a r t i c l e i n f o a b s t r a c t

Article history: Background: Despite a remarkable increase in the depth of our understanding and management of breast cancer
Received 3 November 2016 in the past 50 years, the disease is still a major public health problem worldwide and poses significant challenges.
Received in revised form 28 December 2016 The palpability of breast tumors has facilitated diagnosis and documentation since ancient times. The earliest de-
Accepted 24 January 2017 scriptions of breast cancer date back to around 3500 BCE. For centuries to follow, theories by Hippocrates
Available online 27 January 2017
(460 BCE) and Galen (200 CE), attributing the cause of breast cancer to an “excess of black bile” and treatment
options including the use of opium and castor oil, prevailed. Surgical resection was introduced in the 18th centu-
Keywords:
Breast cancer
ry. The advent of modern medicine led to the development of novel treatment options that include hormonal,
Hippocrates targeted and chemo-therapies. There are still several therapeutic challenges including the treatment of triple
Tamoxifen negative breast cancer (TNBC), and overcoming drug resistance.
Angelina Jolie Scope of review: The increased incidence and awareness of breast cancer has led to significant changes in
Herceptin diagnosis and treatment in recent decades. But, mankind has come a long way. Herein, I have traced how our
Radical mastectomy understanding of breast cancer has evolved from the early description of the disease around 460 BCE as “black
Mammography bile-containing crab-like tumors” to the conventional as a heterogeneous disease with high degree of diversity
Aromatase inhibitors
between and within tumors, as well as among breast cancer patients. How is breast cancer treated today and
BRCA1 and BRCA2
how do risk factors, breast cancer subtype and drug resistance contribute to the therapeutic challenges at the
ER
HER2 turn of the 21st century?
Triple negative breast cancer (TNBC) Major conclusions: Breast cancer remains a serious public health issue worldwide. However, appreciable growth
in our understanding of breast cancer in the past century has led to remarkable progress in the early detection,
treatment and prevention of the disease. The clinical focus is shifting more towards tailored therapy as more tar-
gets are characterized and novel highly innovative approaches are developed.
General significance: Tracing the history of breast cancer, highlights how increased awareness of the disease, and
progress in research and development have enhance our understanding of the disease.
© 2017 The Author. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
2. 3500 BCE–400 BCE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
2.1. Ancient Egypt and Greece . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
2.2. Hippocrates: The humoral theory of medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
3. 0–200 CE: Galen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
3.1. The Galenic humoral theory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
4. 1600–1799 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
4.1. The lymph theory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
4.2. Occupational medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
4.3. Removal of the tumor to prevent “metastasis” . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
5. 1800–1899 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
5.1. Cancer originates from normal tissue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
5.2. Radical mastectomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
5.3. The anti-hormonal theory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69

E-mail address: [email protected].

http://dx.doi.org/10.1016/j.bbacli.2017.01.001
2214-6474/© 2017 The Author. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
 K.E. Lukong / BBA Clinical 7 (2017) 64–77 65

6. 1900–1999. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
6.1. Breast cancer risk factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
6.2. Radiotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
6.3. Mammography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
6.4. Randomized trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
6.5. Breast cancer awareness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
6.6. Breast cancer foundations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
6.7. Tamoxifen for breast cancer therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
6.8. BRCA1 and BRCA2 mutations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
6.9. Herceptin approval (1998) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
7. 2000–2016. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
7.1. The human genome project . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
7.2. Breast cancer subtypes identified . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
7.3. New genetic tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
7.4. New class of drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
7.4.1. Fulvestrant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
7.4.2. Aromatase inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
7.4.3. HER2 inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
8. The Angelina Jolie effect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
9. Novel strategies for HER2-positive cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
9.1. Combination therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
9.2. “Armed antibody drug” . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
10. Trends in research and therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
11. Drug resistance – A major challenge . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
12. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
Transparency document . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75

1. Introduction developing countries is likely due to the increasing adaptation of risk

factors associated with the Western lifestyle [6].
Breast cancer is characterized by uncontrolled growth of malignant Humankind has struggled to understand and treat breast cancer
cells in the mammary epithelial tissue. The disease affects both genders. since the earliest documentation more than 3500 years ago. The visible
Breast cancer is the most frequent type of cancer in women worldwide, signs and symptoms of breast cancer and the palpability and tangibility
with an incidence that rises dramatically with age. Breast cancer report- of the lumps at later stages of the disease have enabled easy diagnosis
edly accounted for 29% of all new cancer cases and 14% of all cancer-re- by physicians in almost every period of recorded history. Despite the
lated deaths among women worldwide up to 2012 [1]. This translates noticeable manifestation of the disease since ancient times, e.g. the Pyr-
into about 1.7 million new cases in women and an estimated 522, 000 amid Era, and the high mortality associated with the advanced form of
deaths in 2012 [2]. As alarming as it may seem, the mortality to inci- the disease, cultural and sexual connotations regarding the breast
dence ratio for breast cancer is around 0.31, which is far more favorable have stigmatized discussions of the disease in the general public and
than pancreas and liver cancers, with ratios of 0.98 and 0.95, respective- limited its description to clinical journals and textbooks until recently.
ly [2]. Breast cancer in the 21st century is therefore not necessarily ter- Besides, from the ancient civilizations and through the 18th and 19th
minal. Better therapeutic options and major improvements in public centuries it was recognized that breast cancer could not be cured once
health and care have resulted in a dramatic reduction in mortality and the cancer had spread.
a major increase in longevity. Breast cancer is rare in males, comprising In many cultures, breast cancer is still considered a taboo subject. As
1% of all breast cancer diagnoses in the United States and less than 0.1% a result, many patients are reluctant to candidly discuss their disease or
of cancer-related deaths in men [3]. its symptoms. However, moral and ethical reforms have been intro-
Since 1999, incidence rates of breast cancer have stabilized among duced in several societies and breast cancer topics are an open discus-
women aged 50 or over, which may reflect trends in mammography sion in all forum or media today. Further, with the advent of electronic
screening rates. Epidemiological data from the United States show media and the Internet, online discussions on the awareness of the dis-
that breast cancer death rates were stable from 1980 to 1989 for ease are now accessible even to the remote areas and cultures of the
women aged 20 to 64 and increased for women aged 65 and over. In world. The pink symbol of breast cancer, adopted in the early 1990s,
most countries, however, breast cancer incidence rates are increasing, represents the international symbol of breast cancer awareness and is
including in countries with historically higher rates, such as those in used by various breast cancer organizations to promote breast cancer
Europe, as well as regions with historically lower incidence rates like awareness and to support fundraising campaigns.
many countries in Latin America, Asia, and Africa [4]. This rise is gener- Our clinical understanding of breast cancer dramatically improved
ally due to changes in reproductive patterns such as age at menarche, from its early description around 460 BCE as “black bile-containing
age at first pregnancy, number of births, and duration of breastfeeding crab-like tumors” to the conventional or modern description as a het-
[5]. The historically higher increase in breast cancer incidence in devel- erogeneous disease that displays diversity in histopathology, genetic
oped countries is largely due to factors associated with economic devel- variation, molecular subtype and clinical outcome. In addition, scientific
opment and urbanization including obesity, consumption of processed discoveries in recent decades have led to new and better ways to pre-
foods, physical inactivity, and changes in reproductive patterns (de- vent, detect, diagnose, and treat breast cancer. This review traces the
layed childbearing; having fewer children; earlier age at menarche; evolution of breast cancer through the various periods of recorded his-
and shorter duration of breastfeeding). The rising incidence in tory. The historic milestones punctuating the progress of our
66 K.E. Lukong / BBA Clinical 7 (2017) 64–77

understanding of breast cancer from ancient times to its current state breast,” which likely meant the swellings were spreading over his
are illustrated in the timeline in Fig. 1. chest [9] (Fig. 2). The surgeon stated that there was no treatment, al-
though cauterization with a fire stick had been performed in one case
2. 3500 BCE–400 BCE (Reviewed in [10]). Other sources, including cuneiform tablet medical
texts from Assyria, and writings from Indian Susruta and other Greek
2.1. Ancient Egypt and Greece medical authorities, mentioned the occurrence of the “bulging” of the
breast. Although this description is highly suggestive of cancer, it may
Origins of the medical papyri: Ancient Egyptians were the first to de- well have indicated mere symptoms of abscess or benign tumors. None-
scribe breast tumors around 3500 years ago in two distinct papyri: The theless, historical writings from India mention the treatment of “breast
Edwin Smith Surgical Papyrus and the Ebers Papyrus. The Edwin Smith cancers” with surgical excision, cautery and arsenic compounds [10–
Surgical Papyrus (named after an American antiques dealer residing in 15].
Cairo in the mid-1800s) is regarded as one of the most important med-
ical documents in the ancient Nile Valley. The papyrus document was 2.2. Hippocrates: The humoral theory of medicine
produced in the Pyramid Age sometime between 3500 and 2500 BCE
that is around the Stonehenge era [7]. The Ebers Papyrus, was named In 460 BCE, the famed Greek physician Hippocrates (460–370 BCE)
after the Egyptologist George Ebers, who purchased it in 1872 and (Fig. 3), widely regarded as the father of Western Medicine, described
later published a facsimile with an English-Latin vocabulary of the doc- breast cancer as a humoral disease. He had postulated (incorrectly)
ument in 1875. that the body consisted of a balance four “humors” that included
Both the Edwin Smith and Ebers papyri contain descriptions of con- blood, phlegm, yellow bile, and black bile, which represented the build-
ditions that are consistent with modern descriptions of breast cancer. ing blocks of nature (air, fire, earth, and water, respectively). He rea-
However, the Ebers Papyrus was more comprehensive and unlike the soned that diseases or even death result from an imbalance in the
Edwin Smith Papyrus, it consists myriad of medical texts arranged in sec- system of humors. According to Hippocrates, the excess of black bile
tions pertaining to specific medical ailments and declaration of the diag- caused breast tumors, and if left untreated the tumor would harden
nosis, prognosis and treatment options at the time. The Ebers Papyrus and eventually rupture, releasing the black fluid to the rest of the
described the “swelling (tumor) of vessels,” with no specific reference body. He coined the term karkinos, a Greek word for crab, to describe
to the breast. However, in the Edwin Smith surgical papyrus an un- the crab-like appearance of tumors. He advised against surgical treat-
named ancient Egyptian surgeon described a total of 48 cases, eight of ment because he considered the procedure to be more life-threatening
which were related to breast tumors or ulcers [8]. Case 39, for instance, than no treatment at all [16]. Hippocratic physicians in the 4th century
describes a patient with a tumor that has “prominent head in his BC are also credited with the first use of the term karkinoma or

Fig. 1. Timeline: The evolution of breast cancer: 3000 BCE to 2016.

 K.E. Lukong / BBA Clinical 7 (2017) 64–77 67

3. 0–200 CE: Galen

3.1. The Galenic humoral theory

In 200 CE, Galen (131–203 CE) (Fig. 4) provided a detailed descrip-

tion of abnormal growth in the breast. He noted that although cancer
can occur in any part of the body, it was more prevalent in the female
breasts, especially in women who were not menstruating or had abnor-
mal menstrual cycles. Like Hippocrates, he believed that breast cancer
was caused by accumulation of “black bile formed in the liver during
hematosis” that was not eliminated by the spleen. Galen also noted
that the tumors with dark-colored veins around them gave a “crab-
like” appearance [16,18]. He proposed that a discharge of the black
bile in ulcerated tumors was the cause of illness arising from breast can-
cer. Roman physicians in the first century routinely and crudely excised
affected breasts with a hot cautery in a procedure that sometimes re-
moved the pectoralis muscles [19]. Galen suggested several other treat-
ment options including a form of lumpectomy in which an incision was
made around the tumor and the entire mass excised. He further advised
physicians to “thin” the blood first with the aid of purgative medica-
ments prior to performing the surgical operation, and he cautioned
that hemorrhage might occur during the operation [16,18,20]. The
crude and horrifying tumor/breast excision methods, without anesthe-
sia, were practiced throughout the Middle Ages. Devices such as Gerard
Tabor's mastectomy instrument were used for rapid extirpation of the
breast (Fig. 3) [21]. Galen also suggested the use of medications like
opium, castor oil, licorice and sulfur. However, all through the Middle
Ages the study of the human body was forbidden for religious reasons.
In fact, the Catholic Church discouraged surgery of large tumors in
1162 and favored treatment with sulfuric acid, for example [21].
Fig. 2. The Edwin Smith Papyrus: a) Case 39 of the original in hieratic. b) The
corresponding modern scientific transcription into hieroglyphics. The images were
cropped from the original publication by Breasted. They contain descriptions of tumors 4. 1600–1799
with prominent heads in the breast of the patient as transliterated in Harding's
publication in 2007. (Harding, F. J. Breast Cancer: Cause, Prevention, Cure. Tekline 4.1. The lymph theory
Publishing, 440 (2007)).

Several physicians and philosophers challenged the Galenic humoral

theory at the beginning of the 17th century. After the discovery of the
carcinoma, which referred to swellings that appear to be malignant or lymphatic system by Olof Rudbeck (1630–1708) of Sweden in 1652,
non-healing swellings, or to ulcerous formation [16]. Hippocrates de- René Descartes (1596–1650) (Fig. 4) proposed the lymphatic theory
scribed lesions of the skin, stomach, cervix and rectum, with no direct for the origin of breast cancer, which contradicted the prevailing hu-
reference to breast cancer except for an Abdera case that was character- moral explanation [22]. In 1680, Dutch professor Francois de la Boe
ized by bloody fluid flowing from the nipple. We know today that most Sylvius, also called Franciscus Sylvius (1614–1672), argued that cancer
nipple discharge or secretions are symptomatic of breast cancer [17]. was not caused by accumulation of black bile. Like other diseases caused
by chemical imbalances that resulted in excess of acid or an excess of al-
kali in the blood, cancer was believed to result from the transformation
of lymphatic fluids to acidic base [23,24]. In the 1730s, Paris physician
Claude-Deshais Gendron (1663–1750) also opposed the humoral theo-
ry of Galen and argued that cancers were “nerve-like” and developed
when nerves and the glandular tissue mixed with lymph vessels (The
History of Cancer: An Annotated Bibliography, by James Stuart Olson).
John Hunter (1728–1793) perpetuated the lymphatic theory of the ori-
gin of breast cancer by extrapolating that the coagulation of defective
lymph led to palpable breast tumors. Hunter is credited as the father
of scientific surgery because he advocated the removal of the cancer
along with the lymphatic spread 100 years before William Halsted in-
troduced radical mastectomy in 1882 (see the Radical mastectomy
section).

4.2. Occupational medicine

In 1713, Bernardino Ramazzini (1633–1714) (Fig. 4), credited with

establishing the field of occupational medicine [25], noted a higher fre-
quency of breast cancer in nuns in Italy than in married women. He
Fig. 3. The mastectomy instrument of Gerard Tabor described in 1721: Image adapted
blamed the disparity on celibacy and speculated that the lack of sexual
from Cotlar, A. M., Dubose, J. J. & Rose, D. M. History of surgery for breast cancer: radical to intercourse or the “unnatural” state caused instability of reproductive
the sublime. Curr Surg 60, 329–337, doi:10.1016/S0149–7944(02)00777-8 (2003). organs like the breast that may lead to decay and the development of
68 K.E. Lukong / BBA Clinical 7 (2017) 64–77

Fig. 4. Cancer and breast cancer pioneers: 400 CE – 1900. a) Hippocrates (engraving by Peter Paul Rubens, 1638https://en.wikipedia.org/wiki/Hippocrates); b) Galen (Source: http://
famousbiologists.org/galen/); c) René Descartes (Source: Hammond, N. (2006). Descartes - The life of Rene Descartes and its place in his times. Tls-Times Lit Suppl, 27–27); d)
Bernardino Ramazzini (source: http://www.britannica.com/biography/Bernardino-Ramazzini); e) Henri François Le Dran (source: https://pictures.royalsociety.org/image-rs-10246); f)
Johannes Peter Müller (source: http://www.britannica.com/biography/Johannes-Peter-Muller); g) William Stewart Halsted (source: Rutkow, I.M. (2000). William Stewart Halsted -
Moments in surgical history. Arch Surg-Chicago 135, 1478–1478.); h) George Thomas Beatson (image from Wellcome Library, London; Photograph by T. & R. Annan & Son; http://
wellcomeimages.org/indexplus/page/Home.html).

cancers [26]. It is now known from recent epidemiological studies that who argued that surgery was the only method to treat breast cancer.
women who nurse their children are less likely to develop premeno- This practice lasted well into the 20th century and eventually led to
pausal breast cancer and therefore the high incidence in nuns reported the application of radical mastectomy or extensive removal of the
by Ramazzini was likely because they did not have children and not be- breast.
cause of celibacy. Another absurd postulation came from Friedrich
Hoffmann of Prussia (1660–1742) and Giovanni Morgagni of Italy 5. 1800–1899
(1682–1771). Hoffmann hypothesized that women who had regular
sex but still developed cancer were practicing “vigorous” sex that caused 5.1. Cancer originates from normal tissue
lymphatic blockage. Morgagni, who was one of the first to perform an
autopsy and to lay the foundation for scientific oncology, theorized that Major advances in human pathology and safety during surgery as
breast cancer was caused by curdled milk. The cause of breast cancer well as progress in oncology marked the 19th century. For instance, in
was also blamed on pus-filled inflammations in the breast (Johanes de 1838, German pathologist Johannes Muller (1801–1858) (Fig. 4) pro-
Gorter, 1689–1762), depressive mental disorders (Claude-Nicolas Le posed that cancer cells developed from the blastema between the nor-
Cat, 1700–1768) and childlessness (Lorenz Heister, 1683–1758). mal tissues and not from the lymphatic system, and later Rudolph
Virchow (1821–1902) demonstrated that tumors were composed of
4.3. Removal of the tumor to prevent “metastasis” cells (Reviewed in [19]). It was during this time that hand-washing
was promoted and the pasteurization technique was invented as a pre-
In the mid-18th century, Henri Le Dran (1685–1770) (Fig. 4), a lead- cautionary measure during surgery. Joseph Lister (1827–1912) intro-
ing French physician, realized that cancer was not a systemic disease but duced the concept of surgical antisepsis using carbolic acid spray;
a local affliction that progressed in stages. In 1757, he proposed the sur- aseptic techniques were adopted for the first time by the Baltic German
gical removal of the breast tumor before it spread to the lymph nodes of surgeon Ernst von Bergmann (1836–1907); and surgical masks and
the armpits. This resonated with the views of Claude-Nicolas Le Cat, sterile rubber surgical gloves were also introduced [19]. However, a
 K.E. Lukong / BBA Clinical 7 (2017) 64–77 69

major progress in surgery occurred on October 16, 1846 when William successful than any other treatment at the time. The first half of the 20th
T. G. Morton (1819–1868) pioneered and publicly demonstrated the use century also saw an explosion of knowledge about the biology and epi-
of ether as anesthesia for surgery [19]. demiology of breast cancer.
To determine whether women undergoing complete or partial sur-
5.2. Radical mastectomy gical resection of the breast experienced prolonged survival compared
with breast cancer patients not undergoing the surgical treatment, in
William Halsted (1852–1922) (Fig. 4), a professor of surgery at Johns 1926 the British Ministry of Health commissioned the first reported
Hopkins Hospital (Baltimore, USA) was a strong proponent of asepsis study to identify “antecedent conditions” (risk factors) to ascertain
during surgical procedures and, like most surgeons at the time, he had how life events impacted the development of breast cancer. Janet
embraced the newly discovered anesthetics. He introduced several Elizabeth Lane-Claypon (1877–1967) (Fig. 5) led this pioneering study
new surgical techniques, most notably radical mastectomy for breast called “A Further Report on Cancer of the Breast.” This landmark study
cancer in 1882. Halsted's operation involved the removal of the whole reported risk factors still considered valid today; specifically pregnancy,
breast as well as the underlying chest muscle (including both pectoralis number of children, age at menopause, age at marriage and duration of
major and minor), and the axillary contents. Halsted later extended his lactation [28]. The study also concluded that surgical treatment at that
operation by removing the supraclavicular lymph nodes after dividing time was more effective in prolonging survival than in previous de-
the clavicle. In 1894, he published the results of the 50 patients he treat- cades, and that “in all countries the proportion of victims of breast can-
ed. He noted a significant decrease in local recurrence to just 6% com- cer who present themselves at a sufficiently early stage of the disease to
pared with the 56%–81% reported in Europe at the time [10]. The main give a good prospect of cure is much too small.” The Lane-Claypon
achievement of Halsted's operation was the reduction of local recur- study, replicated in 1931 by JM Wainwright using information from a
rence rates compared with other procedures. However, it became US cohort with comparable findings [29], was the first modern case-
clear that the operation did not improve overall survival; many patients control study and marked the beginning of a new era of etiologic
who underwent the Halsted radical mastectomy at that time suffered research.
from a relatively advanced stage of cancer. Nevertheless, radical mastec-
tomy became the standard operation for breast cancer worldwide in the 6.2. Radiotherapy
late 19th century and remained the gold standard throughout most of
the 20th century [10]. In 1896 a German physics professor named Wilhelm Conrad
Röentgen (1845–1923) (Fig. 5) described the concept of X-rays, and a
5.3. The anti-hormonal theory few years later X-rays were used for the diagnosis and treatment of can-
cer [30]. Radiation therapy or radiotherapy began with the use of radi-
An overlooked legacy of the 19th century was the discovery that um at low levels. By the 1930, radiotherapy was introduced as a
some breast cancers were hormone-dependent. It had been observed welcomed alternative to radical mastectomy despite the scarcity of ra-
that the growth of breast cancer in patients fluctuated with the men- dioisotopes and its associated hazard. Geoffrey Keynes (1887–1982),
strual cycle, and that growth of the tumor was slower in postmenopaus- surgeon and scholar at St Bartholomew's Hospital in London, developed
al women. In a landmark publication in 1896 entitled “On Treatment of the idea of treating breast cancer by radium implantation. He reported
Inoperable Cases of Carcinoma of the Mamma: Suggestions for a New five-year survival rates of 71% and 29% in stage I and stage II patients, re-
Method of Treatment, with Illustrative Cases,” Thomas Beatson (1848– spectively. George Pfahler from the United States also used radiotherapy
1933) (Fig. 4) reported the observation of temporary regression of met- in the early 1930s and reported a 5-year survival of 80% in patients with
astatic breast cancer in two patients treated by surgical oophorectomy. the stage I disease. In 1948, Robert McWhirter from Great Britain report-
He correctly hypothesized “that internal secretion of the ovaries in some ed the results of a combined use of simple mastectomy followed by ra-
cases favors the growth of the cancer” [27]. This is why he is considered diotherapy in breast cancer treatment [10]. Advances in radiation
the father of anti-hormonal treatment of breast cancer [10]. physics and computer technology during the last quarter of the 20th
century have made it possible to precisely map and target tumors
6. 1900–1999 using techniques such as conformal radiation therapy (CRT), intensity-
modulated radiation therapy (IMRT) and intraoperative radiation ther-
The 20th century saw a retreat from radical surgery, the increased apy (IORT), and the use of radio sensitizers to improve sensitivity of tu-
value of epidemiological studies and the introduction of radiotherapy, mors to radiation.
mammography and chemotherapy. Clinical and fundamental breast
cancer research led to the molecular and pathological classification of 6.3. Mammography
breast cancer, a firm establishment of a hereditary component of breast
cancer. Cooperative research groups amassed large cohorts of patients Before the advent of mammography, early diagnosis of breast cancer
for various studies, and randomized, controlled clinical trials became was limited to palpation or other physical signs such as the retraction or
the norm. Breast cancer was recognized as a major public health issue inversion of the nipples. The discovery of X-rays by Röentgen laid the
in the Western world and stimulated a concerted effort by the public foundations of mammography. In 1913, Albert Salomon, a German sur-
at large in the promotion of breast cancer awareness and the fight geon, conducted a roentgeno-histological study on 3000 mastectomies.
against the disease. He found microcalcifications in X-ray images of tumor samples. His
mammographs provided substantial information about the pathological
6.1. Breast cancer risk factors differences between cancerous and normal tissues [31]. As revolution-
ary as these findings were, mammography did not become a common
Although the Halsted operation was revolutionary, this surgical in- practice until when Raul Leborgne revitalized the interest in mammog-
tervention was becoming controversial and losing popularity among raphy decades later, in 1949 [32]. He initiated imaging quality enhance-
some surgeons. In the mid-20th century there was greater awareness ment and emphasized differential diagnosis between benign and
of the postoperative morbidity that included disfigurement of the malignant calcifications. In 1962, Robert Egan (1920–2002) (Fig. 5)
chest, lymphedema of the arm and occasional irradiation-induced sar- used mammography to diagnose 53 cases of occult breast cancer [33].
comas. Some new breast cancer patients were inclined to choose alter- The mammography technology has thus evolved from film-screen to
native treatments and even some surgeons were becoming increasingly computer-aided digital mammography in the beginning of the 21st
critical of radical mastectomy although it was considered to be far more century.
70 K.E. Lukong / BBA Clinical 7 (2017) 64–77

Fig. 5. Cancer and breast cancer pioneers: 20th century. a) Wilhelm Conrad Röntgen (source: http://www.britannica.com/biography/Wilhelm-Rontgen); b) Geoffrey Keynes (Source:
http://www.modern-humanities.info/people/Keynes_Geoffrey.htm); c) Janet Elizabeth Lane-Claypon (source: http://www.centenary.mrc.ac.uk/news/tales-from-the-century-janet-
lane-claypon-and-epidemiology/); d) Robert Egan. (source: http://onlinelibrary.wiley.com/, in the transcript of an interview titled Mammography and Diseases of the Breast); e)
Bernard Fisher (Source: http://drbarronlerner.com/, in an article titled: Bernard Fisher's Battle Against the Radical Mastectomy).

6.4. Randomized trials based on science rather than on anatomic and mechanistic principles.”
[36].
Dr. Bernard Fisher (1918) (Fig. 5), Professor of Surgery at the Univer-
sity of Pittsburgh, is widely credited with bringing clinical trials and sta- 6.5. Breast cancer awareness
tistical methodology to breast cancer research. He expressed the need to
critically re-evaluate breast cancer treatment. Like Galen, Fisher The 1970s also witnessed the beginning of the breast cancer aware-
asserted that breast cancer was a systemic disease. He hypothesized ness campaign. This movement originated from a general crusade in the
that viable cancer cells tend to disseminate and travel throughout the ‘70s in favor of women's, patients', and consumers' rights. The patients'
circulatory and lymphatic systems, making it impossible to cure cancer right movement propelled the public to acquire medical knowledge,
by surgery alone. Fisher theorized that stray cancer cells could detach question medical authority, take a more central role in medical deci-
from the original tumor site and migrate through the bloodstream or sion-making and demand information about medical procedures. Sev-
lymphatic system to other sites in the body. In these cases, the radical eral important events galvanized the early breast cancer movement.
mastectomy would not be enough. During his tenure as chairman of The book “Our Bodies, Ourselves” was first published in 1971 by Boston
the National Surgical Adjuvant Breast and Bowel Project (NSABP) in Women's Health Collective and republished by New England Free Press
the early '70s, he challenged Halsted's theory and concluded that less- in 1973. The book emphasized the need for women to take full control of
invasive lumpectomy surgery in combination with radiation treated their bodies and provided information about women's health, child-
breast cancer was a more effective option than highly mutilating radical birth, sexuality and lifestyle. In 1974, the First Lady of the United States,
mastectomies. Rose Kushner (see Breast cancer foundations section) and Betty Ford (1918–2011) (Fig. 6) was diagnosed with breast cancer. She
other breast cancer patients rallied behind a trial by Fisher comparing is credited with raising awareness because she discussed her disease
the radical mastectomy to the lumpectomy. Fisher published several candidly with the public. Addressing the American Cancer Society in
randomized trials from the mid-1980s and concluded that radical mas- New York City on November 7, 1975, she concluded that: “My illness
tectomy was not necessary given that the survival rates of women re- turned out to have a very special purpose - helping save other lives,
ceiving lumpectomy with radiation and chemotherapy were the same and I am grateful for what I was able to do.” This attitude encouraged
as women undergoing radical mastectomy [34,35]. He was famously many breast cancer survivors to speak about their experiences. More
quoted as saying “for the first time, the treatment of breast cancer was women underwent their first mammograms and started to believe
 K.E. Lukong / BBA Clinical 7 (2017) 64–77 71

Fig. 6. Breast cancer advocacy: Key figures. a) Rose Kushner. American journalist patient and pioneering advocate for breast cancer patients (as published in Lerner, B.H. (2002). Breast
cancer activism: past lessons, future directions. Nat Rev. Cancer 2, 225–230); b) Betty Ford. First Lady of the United States from 1974 to 1977. Breast cancer patient and advocate (adapted
from https://en.wikipedia.org/wiki/Betty_Ford); c) The Susan G. Komen for the Cure logo. Founded in 1982, the “Susan G. Komen for the Cure” is the largest breast cancer foundation in the
United States (source: http://ww5.komen.org/); d) The International symbol of breast cancer awareness. The pink ribbon was inspired by the Susan G. Komen for the Cure in 1991 (source:
http://www.cancer.org/involved/participate/makingstridesagainstbreastcancer/make-a-pink-ribbon-lapel-pin); e) Angelina Jolie. Hollywood actor. Promoted prophylactic mastectomy
(source: http://time.com/3450368/the-angelina-effect/).

that breast cancer was combatable. Another prominent figure in the ‘70s procedures became the norm, and lumpectomies were offered whenev-
was the American breast cancer activist and journalist Rose Kushner er possible. In the early 1980s there was a rapid rise in public awareness
(Fig. 6) [37]. In 1974, she was diagnosed with what turned out to be ter- campaigns on breast health and breast cancer in the United States and
minal breast cancer. She immediately began gathering information on around the world. Public health advocates encouraged women to per-
the disease and the treatment practices. She was stunned that radical form self-examinations of their breasts, and undergo mammography
mastectomy was still common and she strongly opposed the routine and clinical breast examinations [38].
used of the “1-step” procedure in which surgeons had the authority to The Susan G. Komen Breast Cancer Foundation was founded in 1982
decide on the spot to perform immediate radical breast removal on in memory of Susan Komen, who died from the disease at age 36 in
the anesthetized woman. Kushner rebuked physicians for making inap- 1980 (Fig. 6). The signature Komen Race for the Cure was first held in
propriate treatment decisions on anesthetized women. She advocated Dallas in 1983. This was the first time that a road race of that magnitude
for a two-step surgical procedure, which starts with biopsy followed was associated with a cause. The number of participants in the Komen
by surgery a few days later if necessary. This yielded more time for pa- Race for the Cure has grown exponentially since 1983 to millions annu-
tients to come to grips with their diagnosis and even provide personal ally. The mandate of the Komen foundation today is “To save lives and
input into the treatment options. Kushner was vindicated in 1979 end breast cancer forever by empowering others, ensuring quality
when the National Institutes of Health (NIH) concluded that radical care for all and investing in science to find the cures” (http://ww5.
mastectomy was no longer appropriate. komen.org). Similar funding agencies including the Canadian Breast
Cancer Foundation (since 1986, http://www.cbcf.org) have been
6.6. Breast cancer foundations established worldwide to raise awareness, mobilize action on breast
cancer and collect funds for breast cancer research. A series of develop-
Breast cancer advocacy became mainstream in the 1980s and has ments championed by the breast cancer advocacy occurred in the early
raised awareness and increased focus on public education through var- 1990s. For example, the pink ribbon became the symbol for the revolu-
ious campaigns ever since. Many changes in breast cancer management tion against breast cancer (1991) (Fig. 6), the U.S. Department of the
and funding have directly resulted from the movement or have been Army breast cancer research program was established (1992) and the
fostered indirectly by it [38]. The Rose Kushner two-step surgical Mammography Quality Standards Act became a law in 1992.
72 K.E. Lukong / BBA Clinical 7 (2017) 64–77

6.7. Tamoxifen for breast cancer therapy 6.9. Herceptin approval (1998)

The 1980s were a significant era in drug discovery; a mainstay anti- 1974 marked the identification of a protein called the epidermal
estrogen drug Tamoxifen was approved. Estrogens are hormones that growth factor receptor (EGFR). This protein was the first receptor tyro-
regulate mammary gland development and the female menstrual sine kinase discovered by Stanley Cohen et al. [49]. In 1984 and 1986,
cycle, and are essential for successful reproduction. As described earlier, Ullrich and Coussens (Genentech, USA) and Yamamoto et al. [50] cloned
in the 1890s, before estrogen was discovered in 1929 [39], physicians the HER2 (human epidermal growth factor 2) or neu gene. In fact, HER2
observed that there were changes in breast tumor mass in premeno- is part of a four-member EGFR family, which also includes HER3 and
pausal women with breast cancer during the menstrual cycle. In a series HER4. The neu oncogene was cloned, sequenced and mapped to
of elegant experiments in the early 1960s, Jensen and colleagues dem- human chromosome 17 [50]. In 1987, Slamon et al. demonstrated the
onstrated that estrogen bound to a molecule [40], which was later iden- amplification of the neu oncogene in breast cancer and reported that
tified as the estrogen receptor [41]. These were significant discoveries the amplification correlated with poor prognoses in women with breast
because in the 1970s it was demonstrated that breast tumors grew in cancer [51]. In 1988 William Muller et al. demonstrated that targeting
response to estrogen, which intensified the quest for antiestrogen the active form of HER2 to the mouse mammary gland was sufficient
drugs. Scientists at the British pharmaceutical company AstraZeneca to produce malignant tumors that histologically resembled the human
first synthesized a drug called tamoxifen in 1962 to exploit its contra- breast tumor [52]. It was clear at this point that HER2 amplification
ceptive effects [42]. However, tamoxifen was later found to exert anties- was oncogenic in breast cancers.
trogen effects in estrogen receptor-positive breast cancers. It functions In 1989, Axel Ullrich and his colleagues at Genentech showed that a
by blocking the binding of estrogen to the estrogen receptor. However, monoclonal antibody directed against the extracellular domain of HER2
because the drug was also shown stimulate estrogen activity in the en- specifically inhibited the growth HER2-positive breast cancer cells. The
dometrium, it is considered as a partial antiestrogen and therefore clas- humanized antibody against HER2 was produced from Chinese Hamster
sified as a selective estrogen receptor modulator (SERM) [43]. Following Ovary (CHO) suspension culture in 1992. This humanized antibody,
a series of clinical trials in humans, the Food and Drug Administration now called trastuzumab or Herceptin™ entered Phase I clinical trials
(FDA) approved tamoxifen for the treatment of metastatic estrogen re- in 1992 and Phase II in 1993. Phase III was started in 1995 and closed
ceptor-positive breast cancer in 1977. The FDA later approved tamoxi- in 1997. In a fast-track process in 1998, the FDA approved Herceptin
fen as adjuvant therapy for post-menopausal women (1986) and for in combination with paclitaxel as a first-line treatment of HER2-positive
prophylactic use in women at high risk of breast cancer (1998) [42]. Al- metastatic breast cancers, and as a single agent for second and third-line
most 40 years since its approval, tamoxifen is still considered as the gold therapy. Herceptin is described officially by the FDA as “a recombinant
standard for the treatment of all stages of estrogen-receptor-positive DNA-derived humanized monoclonal antibody that selectively binds
breast cancers. with high affinity in a cell-based assay to the extracellular domain of
the human epidermal growth factor receptor 2 protein, HER2.” It was
the first therapeutic antibody targeted at an oncogene to receive FDA
6.8. BRCA1 and BRCA2 mutations approval. In 2006, Herceptin was also approved as part of adjuvant ther-
apy for women with early-stage HER2-positive breast cancer after it
The 1990s and beyond saw a spike in research and development in was demonstrated that the drug remarkably reduced the risk of recur-
breast cancer. By that time, it was clear through familiar clustering rence by more than 50%.
that first-degree relatives of affected individuals were at a higher risk
of developing breast cancer. Several milestones in the ‘90s included 7. 2000–2016
the emergence of taxanes as important chemotherapeutic drugs for
breast cancer treatment (1994); the introduction of bone-building Research in cancer biology in the 1980s and 1990s led to significant
drugs that helped to reduce complications of breast cancer (1995); progress in cancer prevention, early detection, and treatment. More was
the use of sentinel lymph node biopsy to assess breast cancer metastasis learned about cancer in these two decades than in the past centuries.
(1996); and the approval of capecitabine, an oral chemotherapeutic Cancer research in the new millennium is developing on many fronts.
drug (1998). However, two discoveries in the ‘90s that had a great im- The first 15 years in the 21st century have seen progress in gene and
pact on diagnosis and care were: 1) the identification in 1994 of specific protein expression profiling, targeted therapies, immunotherapy, can-
inherited mutations in tumor suppressor genes BRCA1 and BRCA2 that cer genetics, nanotechnology and robotic surgery. Progress in the un-
increased the risks of breast and ovarian cancers (Reviewed in [44]); derstanding of the pathology and molecular biology, as well as the
and 2) the development of the first targeted anti-breast cancer drug, genetic alterations underlying breast cancer development and progres-
trastuzumab (Herceptin) in 1998. sion in the 21st century have led to the pathological and molecular clas-
Substantial developments in molecular biology and genetics acceler- sification of breast cancer and development of new genetic tests, for
ated in the 1990s. This momentum culminated in numerous genetic dis- instance, and enabled scientists to develop novel therapeutic drugs
coveries, notably the publication of the identification of the variants of and strategies for this disease.
two main breast cancer-associated genes, BRCA1 and BRCA2, published
in Science in 1994 by Easton et al. [45] and Wooster et al. [46], respec- 7.1. The human genome project
tively. Carriers of these gene mutations have been shown to display be-
tween a 40% and 80% risk of developing breast cancer by age 70 The “omics” era essentially began in the 21st century, raising expec-
(Reviewed in [47]). Families with a history of both breast and ovarian tations that advances in human genomics and related fields such as
cancers are usually associated with inherited BRCA1 mutations, whereas transcriptomics, proteomics and metabolomics will lead to enhanced
families that include male breast cancer cases are more commonly progress in diagnosis, therapy and disease prevention. The world”'s
linked to BRCA2 mutations. The highest penetrance of these mutations largest collaborative biological project was the sequencing of the
is 36%, found in families of Jewish descent [48]. The three most common human genome, which was completed and reported by the Internation-
mutations in the Ashkenazi Jewish group are BRCA1.185delAG, al Human Genome Sequencing Consortium on April 14, 2003 (www.
BRCA1.5382insC, and BRCA2.6174delT. Groups originating from genome.gov/11006929). This project steered the genomic revolution,
Northern Ireland and the west coast of Scotland tend to harbor a and molecular technologies have diversified since 2003. This has
BRCA1 2800delAA mutation, whereas people from the east coast of opened up strategies to study cancer and discover novel and more effec-
Scotland commonly display a BRCA2 6503delTT mutation [48]. tive diagnostic and therapeutic tools for the disease. Several cancer
 K.E. Lukong / BBA Clinical 7 (2017) 64–77 73

databases were created in the first decade of the 21st century. For in- outweigh the risks.” The assay is a commercially available diagnostic
stance, the Cancer Genome Atlas (TCGA) project, founded in the United multigene expression test. It analyzes the expression pattern or “signa-
States in 2005, uses large-scale genome sequencing and bioinformatics ture” of 21 genes in breast tumor tissues by using Reverse Transcriptase
to catalogue cancer-related mutations, which has improved our under- Polymerase Chain Reaction (RT-PCR). The assay predicts outcomes for
standing of the molecular basis of cancer (http://cancergenome.nih. patients with breast cancer, including the likelihood of chemotherapy
gov/abouttcga). benefit, as well as the probability of breast cancer recurrence and pa-
tient survival within 10 years of diagnosis. The test was clinically vali-
7.2. Breast cancer subtypes identified dated for use in women with early-stage (stage I or II), ER-positive
and lymph node-negative breast cancer, which accounts for more
The molecular classification of breast cancer based on gene expres- than 50% of all women diagnosed with breast cancer [62]. The test re-
sion profiles reported by a few research groups in the first decade of sults display a Recurrence Score ranging from 0 to 100, where the higher
the 21st century is one of the momentous developments in personalized the score, the greater the chances of relapse if a patient is treated with
medicine in recent years. Genome-wide profiling technologies have led hormonal therapy alone. Thus, with this test, oncologists can identify
to a better understanding of the biological heterogeneity of breast can- patients who are in urgent need of lifesaving chemotherapy to prevent
cer. Gene expression profiling of human breast tumors revealed molec- cancer recurrence. Low risk patients who do not need additional che-
ular subtypes with distinct gene signatures and associated clinical motherapy are thus spared the related side effects and unnecessary ad-
outcomes [53–56]. In 2000 Perou et al. published seminal studies on mi- ditional costs.
croarray-based gene expression profiling as a new way of classifying Other tumor-based gene expression-based prognostic models have
breast cancers. These studies used an “intrinsic” gene list to classify been developed [63]. For instance, the FDA approved the MammaPrint
breast cancer into at least four main molecular subtypes: basal-like, test in February 2007. The MammaPrint test is a 70-gene prognostic sig-
HER2 (human epidermal growth factor receptor 2)-positive, luminal A nature with high negative predictive value for distant metastasis for
and luminal B. Luminal A and Luminal B types are both estrogen recep- lymph node negative breast cancer patients of all ages, irrespective of
tor (ER)-positive, whereas the basal-like breast cancers are usually ER- their ER status, and who have tumors of less than 5 cm. This test
negative, progesterone-receptor (PR)–negative, and HER2-negative tu- would generally spare many older breast cancer patients adjuvant treat-
mors (hence, “triple-negative” breast cancers or TNBCs). The basal-like ments [64].
subtype is so defined based on the expression of genes such as
cytokeratins 5 and 17, as well as the epidermal growth factor receptor 7.4. New class of drugs
(EGFR/HER1), characteristic of the outer or basally located epithelial
layer of the mammary gland. HER2-positive cancers display amplifica- 7.4.1. Fulvestrant
tion and high expression of the ERBB2 gene and several other genes of Tamoxifen therapy is usually the first treatment for ER-positive pa-
the ERBB2 (HER2) amplicon. All these subtypes are histologically differ- tients with locally advanced or metastatic breast cancer. As described
ent and tend to vary in their clinical outcomes. The luminal A subtype, earlier, tamoxifen possesses some estrogenic activity, which may
for example, is typically histologically low-grade and has the most fa- cause endometrial hyperplasia or carcinoma and may also predispose
vorable prognosis, whereas luminal B cancers are often high-grade patients to thrombosis. Fulvestrant however is essentially a pharmaco-
and therefore more aggressive. HER2-positive cancers are usually logical antagonist and not a partial agonist like tamoxifen. It is referred
high-grade and are associated with poor prognosis. The basal-like tu- to as a “pure” anti-estrogen. The drug is a selective estrogen receptor
mors are usually the most aggressive and are associated with the down-regulator (SERD) so named because it binds directly to the ER,
shortest relapse-free and overall survival [57]. Basal-like breast cancers preventing ER dimerization and promoting the rapid degradation of
account for 56% to 85% of TNBCs [57]. Some TNBCs lack the gene expres- the receptor [65]. In 2002, the FDA approved Fulvestrant, developed
sion profile of the basal-like tumors and are classified as normal-like by AstraZeneca, as a second-line endocrine therapy “for the treatment
breast cancers. Normal-like breast tumors are usually small and tend of hormone receptor positive metastatic breast cancer in postmeno-
to have a more favorable prognosis [57]. Claudin-low is a more recently pausal women with disease progression following anti-estrogen
described class of breast cancer that is often triple-negative, but distinct therapy.”
in that it expresses low levels of cell-cell junction proteins including
claudin and E-cadherin (Reviewed by [58]). A novel molecular stratifi- 7.4.2. Aromatase inhibitors
cation of the breast cancer by integrated genomic/transcriptomic analy- The ovaries are the principal source of estradiol (estrogen) in pre-
sis revealed 10 integrative breast cancer clusters, typified by well- menopausal women [66]. However, in postmenopausal women the
defined copy number aberrations [56]. All these gene profiling studies ovaries cease to produce estrogen, and the synthesis of estrogens occurs
have drastically altered our conceptualization of breast cancer and pro- in a number of extragonadal sites including the adipose tissue of the
vided a multitude of translational research opportunities to improve di- breast [66]. Estrogens are synthesized in postmenopausal women main-
agnosis, prognostic and therapeutic approaches for this disease. In 2012 ly via conversion of adrenal androgens to estrone and estradiol with es-
the International Agency for Research on Cancer (IARC) published the tradiol being the predominant physiological hormone. Aromatase is an
4th edition of the World Health Organization (WHO) Classification of enzyme that catalyzes the rate-limiting and final step of this estrogen
Tumors of the Breast [59]. This edition included definitions of new his- biosynthesis. Aromatase Inhibitors (AIs) block the function of this en-
topathological diagnosis classifications complemented by recent de- zyme, thus limiting the supply of estrogen that fuels the growth of
scriptions of molecular subtypes, as well as genetics, prognostic and some breast cancers [67]. AIs have been shown to be more effective
predictive features [60]. than the antiestrogen tamoxifen in reducing the risk of breast cancer re-
currence and spread, and are well tolerated. In 2005, the FDA approved
7.3. New genetic tests the drug letrozole (also called Femara), the first in a new class of AI
drugs. Letrozole produced by Norvatis was first approved for long-
In 2004, Genomic Health, in Redwood City, California, introduced the term use in post-menopausal women who have completed five years
Oncotype DX Breast Cancer Assay that enabled a personalized approach of tamoxifen treatment. Clinical trials revealed that the drug reduces
to chemotherapy [61]. Steven Shak, the chief medical officer at Genomic the risk of breast cancer recurrence and spread even more than tamox-
Health noted that the days of “one size fits all,” were over and that “the ifen alone. Anastrazole (produced by AstraZeneca and marketed under
Oncotype DX test now makes it possible to individualize treatments by the trade name Arimidex) is another FDA-approved AI that was shown
making an informed decision on whether the benefits of chemotherapy to improve survival and alleviate the symptoms of cancer for post-
74 K.E. Lukong / BBA Clinical 7 (2017) 64–77

menopausal women with advanced breast cancer [67]. Raloxifene, a called “HER dimerization inhibitors.” This drug binds to HER2 and in-
drug that had been used to prevent and treat osteoporosis in postmen- hibits its homo- or heterodimerization. The combination of pertuzumab
opausal women since 1997, was later shown to be as effective as tamox- with Herceptin and docetaxel, as first-line treatment for HER2-positive
ifen in reducing the risk of developing invasive breast cancer. Raloxifene metastatic breast cancer, has been found to substantially slow cancer
also functions by blocking the effects of estrogen on breast tissue, but growth and significantly improve progression-free survival as com-
cannot, however, be used to treat invasive breast cancer or to decrease pared with combining a placebo with Herceptin and docetaxel. Because
the risk of developing breast cancer [68]. the use of this regimen was not associated with any serious side effects,
this combination therapy represents substantial progress in the stan-
7.4.3. HER2 inhibitors dard of care for HER2-positive patients [75,76]. Additional follow-up
Lapatinib (also known by its trade name Tykerb by manufacturer studies further supported the positive benefit-to-risk ratio in HER2-pos-
GlaxoSmithKline) was FDA-approved in 2007 for HER2-positive pa- itive metastatic breast cancer patients treated with the pertuzumab,
tients whose condition was no longer responsive to Herceptin treat- Herceptin, and docetaxel regimen [75,76]. The result of this study has
ment. About 25% of breast cancers overexpress HER2, and as fueled momentum into research exploring the effectiveness of combin-
mentioned earlier, this overexpression confers a more aggressive phe- ing two or more drugs that target the same signaling pathway.
notype and is associated with a poor prognosis. HER2 is a receptor tyro-
sine kinase that transmits signals to promote several cellular processes 9.2. “Armed antibody drug”
including cell proliferation. Lapatinib inhibits the tyrosine kinase activi-
ty of HER2 and HER1 and thus suppresses signaling by these receptors. Despite the therapeutic advances, the median progression-free sur-
The drug was also approved for use in combination with the drug cape- vival and overall survival of HER2-positive patients treated with
citabine for patients with advanced breast cancer whose tumors trastuzumab alone or in combination with various chemotherapy-
overexpressed the HER2 protein. In 2010, lapatinib was also approved based regimens is 7 months at best. In 2013, the FDA approved a next-
as an initial therapy in combination with letrozole for patients with generation targeted drug called trastuzumab emtansine (T-DM1) after
HER-2 positive breast cancer (Reviewed in [69]). clinical trials including the pivotal EMILIA study demonstrated that T-
DM1 administration extends survival in women with advanced HER2-
8. The Angelina Jolie effect positive breast cancers that progress despite other standard therapies
[77]. T-DM1, also known by its trade name Kadcyla (developed by
Women who have inherited mutations in the BRCA1 or BRCA2 genes Genentech) is a conjugation of two anticancer drugs – the HER2-
have a substantially elevated risk of developing breast and ovarian can- targeted trastuzumab (T) and the chemotherapy drug emtansine,
cer [70]. A multinational study in the first decade of the 21st century which binds to microtubules and inhibits cell division.[78] T-DM1 spe-
was undertaken to determine whether preventive surgery (which in- cifically targets HER2-positive cells in that trastuzumab selectively
cludes mastectomy as well as the removal of the fallopian tubes and binds to subdomain IV of the HER2 receptor at the surface of tumor
ovaries - salpingo-oophorectomy) can reduce the cancer and mortality cells leading to the internalization of this complex by endocytosis and
risk in BRCA1/2 mutation carriers. The general consensus from these subsequent intra-lysosomal proteolytic degradation and the release of
studies was that the use of preventive surgery significantly reduces DM1 into the cytoplasm. The action of DM1 is coupled with the anti-
the risk of breast cancer as well as the risk of ovarian and fallopian tumor activities of trastuzumab, which include antibody-dependent
tube cancers [71]. In general, without the surgery, women with cell-mediated cellular cytotoxicity and inhibition of ligand-independent
inherited mutations in the two BRCA genes have up to an 84% lifetime intracellular HER2 signaling events that promote cell proliferation [79].
risk of developing breast cancer [72]. The improved outcomes seen with T-DM1 has led to the development
In 2013, Hollywood actor Angelina Jolie, a BRCA1 carrier, revealed in of several novel therapies including MM302, an antibody linked to
a Time magazine cover story that she had a prophylactic bilateral mas- pegylated liposomal doxorubicin (NCT01304797) and MM111, an anti-
tectomy (Fig. 6). The publicizing of her experience raised awareness of body fusion protein targeting the HER2/HER3 heterodimer [78]. Pro-
BRCA1/2 testing and cancer prevention, and was met with widespread tein-bound nanoparticle technology is also used now in most cancers.
support. Eventually, the so-called Angelina Jolie effect followed, which In 2013, the FDA approved Abraxane, a Paclitaxel Albumin-stabilized
led to a general increase in referrals to centers for genetic tests [73]. Nanoparticle Formulation. Abraxane delivery spares patients from the
This helped alleviate some of patients' insecurities associated with the side effects such as severe allergic reactions associated with solvent-de-
loss of their sexual identity post-preventative surgery. The Angelina livered taxol.
Jolie effect has underscored the significant impact of a celebrity an-
nouncement in the health care sector. Prophylactic mastectomy certain- 10. Trends in research and therapy
ly minimizes the risk of developing breast cancer within 10 years of the
surgery [74]. The obvious side effects of mastectomy along with The therapeutic options for breast cancer patients have increased
salpingo-oophorectomy for pre-menopausal women are early-onset dramatically in the 21st century with increasing efforts towards the de-
menopause and infertility. velopment of more efficient and effective screening, diagnosis and
treatment options. The landscape of therapy for patients with metasta-
9. Novel strategies for HER2-positive cancers tic breast cancer is also changing. For instance, many ongoing studies
are exploring strategies to overcome endocrine resistance, target TNBC
9.1. Combination therapy and develop new anti-HER2 therapies. There are promising advances
in immunotherapy and new directions in inhibiting aberrant angiogen-
In 2010, the CLEOPATRA (CLinical Evaluation Of Pertuzumab And esis, one of the hallmarks of tumors [80]. Our understanding of the mo-
TRAstuzumab) study, an international, randomized, double-blind, pla- lecular characteristics of tumors in general, coupled with better
cebo-controlled phase III trial that involved approximately 800 HER2- screening methods has helped shape the recent advances in breast can-
positive patients from around 250 centers worldwide, illustrated the ef- cer treatment. Neoadjuvant therapy, for example, has become a stan-
fectiveness of combining docetaxel, trastuzumab (Herceptin), and dard recourse. There are strategies not only for HER2- and ER-positive
pertuzumab or docetaxel, trastuzumab, and placebo in breast cancer cancers, but also new options in the management and treatment of
treatment [75,76]. On June 8, 2012, the FDA approved pertuzumab, de- TNBC patients [81].
veloped by Genentech for the treatment of HER2-positive metastatic Targeting TNBC has been particularly difficult because of
breast cancer. Pertuzumab represented the first of a new class of drugs “druggability” challenges (Reviewed by many including [81–85]).
 K.E. Lukong / BBA Clinical 7 (2017) 64–77 75

Therefore, chemotherapy is still viewed as the clinical state of the art 12. Conclusion
therapy [83]. Nonetheless, different subsets of TNBC have been dis-
tinguished based on various signatures including the expression/ac- Although described more than 3500 years ago, breast cancer re-
tivation of certain proteins, transcripts expression, and genomic mains a serious public health issue, especially with the dramatic and
alterations [84,85]. Some TNBCs are characterized by a deficiency in deleterious shift in lifestyle in most societies. Breast cancer is heteroge-
homologous recombination, which is partly attributed the loss-of- neous in nature at both the epidemiological and molecular levels. Clin-
function of BRCA1 and/or BRCA2 proteins [86]. All these molecular ical and epidemiological evidence has identified many important
features and well as other cellular characteristics have paved the breast cancer risk factors such as age, family history, early menarche
way for identification of potential options for TNBC “targeted” ther- and medical history; factors which are intangible or beyond our control.
apy, some of which are currently being evaluated in various clinical However, about 70% of breast cancers today arise due to risk factors that
trials [84]. The link between TNBC and germline BRCA1 mutations we can change or avoid. These include obesity, lack of exercise, smoking,
has led to the investigation of poly-ADP ribose polymerase (PARP) drinking, and diet, along with factors that may negatively influence a
inhibitors in TNBC. Trials of some PARP-inhibitors including Iniparib woman's hormonal environment such as hormone replacement thera-
in TNBCs have shown improved rates of response and progression- py (HRT) and reproductive history. These rate-limiting steps in the
free survival [87]. Many cancers, including breast cancer, are driven fight against breast cancer must not be overlooked. As highlighted in
by a subset of cells termed cancer stem cells. These are tumor-initiat- this review, appreciable growth in the knowledge of cancer biology
ing cells that can initiate tumor growth as well as mediate tumor me- has led to remarkable progress in the early detection, treatment and
tastasis. Several signaling pathways, such as the STAT3 signaling prevention of cancers in recent years. The increasing focus on tailored
pathway, are known to regulate breast cancer stem cell (BCSC) therapy and the integration of cancer stem cell-based targeted therapies
self-renewal and may therefore be considered as viable therapeutic and immune therapies, together with existing therapeutic methods,
targets [88]. Effective targeting of BCSCs would be beneficial for hold promise for the cure of breast cancer.
TNBCs, which currently have no specific therapeutic targets. The Hippocrates advocated the importance of tailored therapy over
focus on breast cancer treatment is shifting more towards individu- 2500 years ago when he stated that “It is more important to know
alized/tailored therapy, as our understanding of the connection be- what sort of person has a disease than to know what sort of disease
tween the characteristics of the individual patient and the a person has.”
respective tumor continues to improve. Advances in high-through-
put genomic profiling have enabled researchers to catalogue the
Conflict of interest
spectrum of somatic alterations in breast cancers. Genomic profiling
will be valuable for precision and individualized medicine through
The author is unaware of any affiliations, memberships, or financial
accurate diagnosis, prognosis, stratification and better dynamic
holdings that might be perceived as affecting the objectivity of this
monitoring of treatment response.
review.
Several other therapeutic strategies have attracted attention recent-
ly. These include: i) the use of exosomes as potential carriers for deliv-
Transparency document
ering drugs to tumor cells [89]; ii) targeting of long noncoding RNAs
(lncRNAs), and specifically the metastasis-associated lung adenocarci-
The Transparency document associated with this article can be
noma transcript 1 (MALAT1), shown to be also elevated in breast cancers
found, in online version.
[90,91]. Some of the recent technological improvements have provided
more tools in the fight against breast cancer. These new techniques in-
clude marginally invasive treatments such as radiofrequency ablation Acknowledgements
[92] and cryo-ablation [93]. These technologies are still in their infancy;
more research and long-term data collection should clarify their The author thanks Raghuveera Goel (graduate student, Lukong lab)
effectiveness. for his critical review of the manuscript. The author apologizes to those
whose work was not included owing to space limitations. The author al-
so thanks The Beatles for inspiring the title. Breast cancer research in the
11. Drug resistance – A major challenge Lukong lab has been supported by funds from various organizations in-
cluding the Canadian Breast Cancer Foundation (CBCF), (U of S fund no
Current targeted therapies for breast cancer include the use of ta- 416170) and Canadian Institutes of Health Research (CIHR), (U of S fund
moxifen, fulvestrant and aromatase inhibitors for ER-positive breast no 411333).
cancers, and Herceptin and various HER2 inhibitors for the treatment
of HER2-positive breast cancers. Numerous chemotherapeutic drugs References
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