August 2024 SOCRA Source Journal - Journal - Page 44
and ER+ tumours includes the
existence of two independent
pathways of carcinogenesis.
Meaning, all tumours that
develop through a single
pathway resulting initially in ER+
neoplasms can be transformed
into ER– tumours by epigenetic
and /or genetic events (Zhu
et al. 1997). The maintenance
of the original receptor status
of breast cancer over time
reveals that the etiology of
receptor negative and receptor
positive cancer is distinct
and can diverge early in the
pathogenesis of these tumours.
2. Statistical Studies of TNBC
This literature review reveals that
the earliest indication of TNBC
was in 2005. Foulkes et.al (2010)
stated that TNBC has a growing
recognition by oncologists,
geneticists, and pathologists.
TNBC is a heterogeneous type
of malignancy associated with
poor prognosis and accounts
for between 9% and 16% of all
breast cancer cases (Montagna
et al. 2013, Siegel et al. 2015).
DeSantis et al. (2014) found that
women with TNBC were dying
more frequently than patients
with other subtypes of breast
cancer (42.2% versus 28%
respectively), while the median
time to death was 4.2 years for
patients with TNBC compared
with 6 years for those with
other cancers.
Gluz (2009) explained that
there were no universally
accepted models explaining the
factors which drive the TNBC
development. Previous research
has found the aggressiveness
of TNBC is further indicated
by the fact that the peak risk
of recurrence is within the
昀椀rst three years after initial
44
treatment of the disease with
the majority of deaths occurring
in the 昀椀rst 昀椀ve years (Dent et
al. 2007). Many studies are
increasingly recognizing that
TNBC is an aggressive disease
with outcomes inferior to those
of other breast cancer subtypes
based on the gene expression
pro昀椀le and the luminal androgen
receptor (approximately LAR,
12%) (Hubalek et al. 2017).
The rate of survival is highest
for the ER-positive, PR- positive
and HER2 positive phenotypes.
According to the American
Cancer Society breast cancer
statistics from 2013-2015 (Siegel
et al. 2013) (which included data
on incidence, mortality, survival,
and screening) there were
roughly 232,340 new cases of
the invasive disease with 39,620
related deaths in the US. Yearly,
there are 54,000 breast cancer
cases diagnosed in the UK and
the survival rate for this disease
is lower than in comparable
industrial countries. (Perou et al.
2000, Siegel et al. 2016).
Also, the heterogeneous nature
of breast cancer has important
implications for physicians and
their patients (Onitilo et al.
2009). Moreover, many studies
in gene expression analysis
suggest that TNBC arises from
basal cells of the mammary
epithelium and is associated with
high mitotic activity and invasive
tumours in younger patients
and in premenopausal women
(Greenwood et al. 2012, Sørlie et
al. 2001). Approximately 75% of
breast cancer is positive for ERα
and/or PR protein expression.
The remaining 20% - 25% of
breast cancers are ERα and PR
negative and are not amenable
to selective oestrogen receptor
SOCRA SOURCE © May 2024
modulators. However, few
tumours in the triple negative
group can express AR and the
type of expression seems to be
related to tumours undergoing
apocrine differentiation; this
observation has important
biological and chemical
signi昀椀cance (Niemeier et al. 2010).
3. Molecular Subtypes of TNBC
Many clinical studies have
revealed that triple negative
breast cancer is a heterogeneous
disease at the molecular, clinical
and histological levels (Lehmann
and Pietenpol 2015, Pareja et al.
2016). Molecular medicine and
advanced biotechnologies such
as next generation sequencing
have led to the discovery of
several molecular characteristics,
including the inactivation of the
BRCA pathway, MAP/ERK kinase
(MEK) and phosphatidylinositol-3kinase (PI3K) pathway activation,
high level of tumour protein P53
mutations, loss of retinoblastoma
protein (RB), high activation
of MYC, and enrichment for
androgen receptor (AR) regulated
gene expression signatures.
Some potentially targetable
molecules include the immune
checkpoints Programmed Death
(PD1) and Programmed DeathLigand 1(PDL1). Understanding of
the molecular pro昀椀les of different
types of tumours has permitted
and allowed the development
of promising therapeutic agents
such as DNA-damaging agents,
AR inhibitor and Immune
checkpoint inhibitors (Oualla et
al. 2017).
Zheng et al. (2012) observed
that several strategies have
demonstrated that basal-like
tumours are not necessarily
TNBC. For instance, between
15% and 45% of basal-like