Beyond 5 years: enduring risk of recurrence in oestrogen receptor-positive breast cancer

Reviews
Beyond 5 years: enduring risk
of recurrence in oestrogen
receptor-positive breast cancer
Juliet Richman * and Mitch Dowsett
Abstract | Women with early-stage oestrogen receptor (ER)-positive (ER+) breast cancer who
receive standard endocrine therapy for 5 years remain at risk of distant recurrence for at least
15 years after treatment discontinuation. The extension of the duration of adjuvant endocrine
therapy to 10 years has been shown to reduce the risk of recurrence only in a subset of women
and, to date, predictive biomarkers of benefit from therapy do not exist. In this Review, we briefly
explore the epidemiology of late recurrence (>5 years after diagnosis) in patients with ER+ breast
cancer. The mechanisms underlying this phenomenon remain poorly understood; we discuss the
evidence currently available on processes such as alterations of gene expression or specific
genomic aberrations and examine several models used for risk prognostication and for
estimating the presence of minimal residual disease, as well as the relevance of these prediction
tools for clinicians and patients. Our aim is to enable clinicians to make well-informed decisions
on whether to extend endocrine therapy for each individual patient.
Ralph Lauren Centre for
Breast Cancer Research,
Royal Marsden Hospital,
London, UK.
*e-mail: juliet.richman@
icr.ac.uk
https://doi.org/10.1038/
s41571-018-0145-5
296 | MAY 2019 | volume 16
A unique tenet of oestrogen receptor (ER)-positive
(ER+) breast cancer is its ability to recur up to 20 years
after diagnosis1,2. Unlike many other cancers, including
ER-negative (ER−) breast cancer, the recurrence risk of
ER+ breast cancer remains stable beyond 5 years after
diagnosis. This means that 4,000–5,000 distant recurrences beyond 5 years can be expected among the
~46,000 new cases of ER+ breast cancer diagnosed in
the UK in 2015 (refs3,4) (Fig. 1). The overall incidence of
invasive breast cancer is projected to reach >71,000 new
cases per year in the UK in 2035 (ref.5) and ~280,000
new cases per year in the USA by 2030 (ref.6). Late
recurrence, therefore, is and will remain a considerable
health problem in the foreseeable future. In this Review,
we define late recurrence as recurrence beyond 5 years
from diagnosis.
Several unanswered questions surround late recurrence, such as whether differences other than the time
elapsed after diagnosis exist between early and late
recurrence and, if so, whether late recurrence can be
better prevented by defining different patient subgroups according to risk of recurrence. In this Review,
we explore the importance of late recurrence as an entity.
We discuss the methods currently used to estimate risk
of late recurrence and the validity and utility of prognostic biomarkers and aim to provide guidance for clinicians on how to incorporate these methods into clinical
practice in order to make decisions that improve the
outcomes for patients with ER+ breast cancer.
Adjuvant endocrine therapy
Endocrine therapy, aimed at suppressing oestrogen signalling, is recommended at diagnosis and for at least
5 years in virtually all women with ER+ primary breast
cancer owing to the survival benefits derived from
this therapeutic modality. In postmenopausal women,
treatment with tamoxifen or aromatase inhibitors for
5 years is associated with an ~30% or an ~40% reduction,
respectively, of mortality from breast cancer7. Several
studies have addressed the question of whether patient
outcomes would be improved with an extension of
endocrine therapy beyond 5 years (Table 1).
Tamoxifen beyond 5 years
From the late 1990s, the recommendation has been to
cease tamoxifen treatment at 5 years because, in the
NSABP-B14 study8, patients with early-stage ER+ breast
cancer who received 5 years of placebo later had a significant improvement in disease-free survival (DFS) over
those who received further tamoxifen (82% versus 72%;
P = 0.03); a trend (not significant) towards improved
overall survival (OS) was also observed in the same
group (94% versus 91%)8. Over the past 5 years, data
from two studies with larger cohorts9,10 subsequently
showed a benefit of tamoxifen beyond 5 years. In the
ATLAS study9, an absolute reduction in disease recurrence (21.4% versus 25.1%; P = 0.002) and reduced breast
cancer-related mortality (12.2% versus 15%; P = 0.01)
at 10 years of follow-up were observed in patients
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Key points
• Oestrogen receptor (ER)-positive (ER+) breast cancer is at least as likely to recur
beyond 5 years as it is before 5 years from diagnosis.
• Extended endocrine therapy is likely to improve survival in a subgroup of women with
ER+ breast cancer; all women should be evaluated for their likely risk of recurrence at
the completion of 5 years of endocrine therapy.
• Clinical and genomic expression models can help stratify patients for their risk
of late recurrence, but most are not predictive of benefit from extended endocrine
therapy.
• Dormancy of ER+ breast cancer occurs through a multitude of mechanisms;
microscopic disease can emerge from dormancy in some women in response to
unidentified triggers.
• Monitoring of minimal residual disease through circulating tumour cells and
circulating tumour DNA is likely to prove beneficial for anticipating late recurrence.
• An individualized, patient-centred approach to long-term risk management is
essential owing to the protracted length of survivorship and its ensuing complexity.
receiving an additional 5 years of tamoxifen compared
with those who stopped treatment at 5 years. The difference between the extended tamoxifen and placebo
arms became more apparent after 10 years of follow-up,
highlighting the importance of long-term follow-up
durations in studies involving use of adjuvant therapy.
The incidences of pulmonary embolism and endometrial cancer were significantly higher among patients
in the extended therapy group than in the discontinuation group (Table 1). These findings were consistent
with those from the UK-based aTTom study10, in which
patients with ER+ breast cancer who received tamoxifen
for up to 10 years had a significant reduction in disease recurrence (16.7% versus 19.2%; P = 0.003) and a
nonsignificant trend towards reduced overall mortality
(24.5% versus 26.1%) compared with those who underwent tamoxifen discontinuation at 5 years. Consistent
with the ATLAS study, incidence of endometrial cancer was significantly greater compared with those who
discontinued tamoxifen at 5 years.
Aromatase inhibitors beyond 5 years
In the pivotal MA.17 study11, women who had received
5 years of adjuvant tamoxifen were randomly allocated
to receive either the aromatase inhibitor letrozole or
placebo for up to 5 years. Letrozole treatment was
un­equivocally associated with an absolute reduction in
the risk of recurrence of 4.6% (HR 0.58) compared with
placebo. The incidence of toxicities was largely comparable in the two trials. Women receiving letrozole
experienced significantly more hot flushes and arthralgia and/or myalgia than those receiving placebo. A significantly greater incidence of new-onset osteoporosis
was observed in the letrozole arm than with placebo
(8.1% versus 6.0%; P = 0.003), but this difference did
not translate into an increased rate of bone fractures.
The aromatase inhibitor exemestane was tested in a
study with a similar design, NSABP-B33 (ref.12), in
which therapy extension with an aromatase inhibitor
was associated with improvements in 4-year DFS (91%
versus 89%; P = 0.07) and in 4-year relapse-free survival
(96% versus 94%; P = 0.004) compared with placebo.
The incidence of toxicities was similar to that observed
in MA.17 (ref.11).
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The benefits of extending a 5-year course of adjuvant
aromatase inhibitors appear to be less substantial. In the
MA.17R study13, 1,918 women without disease recurrence after 5 years of therapy with letrozole were randomly assigned to receive either letrozole or placebo for
a further 5 years. An absolute reduction in disease recurrence of 3.3% was seen in the letrozole group, but this
difference was weighted heavily in favour of a reduction
in the incidence of contralateral second cancers. Patients in
the letrozole group had a higher incidence of osteo­
porosis and skeletal-related adverse events; the incidence of other toxicities was unremarkable. In the DATA
study14, a borderline significant improvement in 5-year
DFS (83.1% versus 79.4%; P = 0.066) and no improvement in OS (90.8% versus 90.4%; P = 0.6) were observed
with 6 years versus 3 years, respectively, of anastrozole
following 2–3 years of tamoxifen. Nevertheless, in post
hoc analyses, a subgroup of patients with both ER+ and
progesterone receptor-positive disease with lymph
node involvement in the 6-year treatment group had
improved outcomes. In the IDEAL study15, 5 years
of treatment with letrozole was not superior to 2.5 years of
treatment after an initial 5 years of endocrine therapy;
no prognostic subgroups or biomarkers were identified
in this study. Furthermore, the analysis of DFS events in
IDEAL showed that the main differences in outcomes
between treatment arms were related to second breast
cancers and not to distant disease.
Taken together, these results suggest that postmenopausal women who have received 5 years of tamoxifen
and switch to an aromatase inhibitor are those most
likely to derive benefit from extended endocrine therapy. For those who have received 5 years of therapy
with an aromatase inhibitor, the benefits appear modest
and, therefore, appropriate patient selection methods
are clearly needed. Endocrine therapy is cost effective
and often well tolerated, and thus therapy extension
beyond 5 years should only be avoided in patients with
the lowest risk of recurrence. In some patients, however,
toxicities can be substantial and must be considered in
decisions regarding treatment extension.
Future of adjuvant therapy
The majority of distant recurrences seen after 5 years
of endocrine therapy cannot be prevented by extending
treatment beyond the initial 5 years; thus, other treatments are needed for this purpose. In a neoadjuvant
study, the addition of the mTOR inhibitor everolimus
to letrozole was associated with a trend towards higher
overall response rates than letrozole plus placebo (68.1%
versus 59.1%; P = 0.062)16. The results of an ongoing
adjuvant trial of this combination (NCT01674140)
might show improved outcomes. Results from studies of other agents in the adjuvant setting, such as the
CDK4/6 inhibitors palbociclib (tested in the PALLAS
trial: NCT02513394) and abemaciclib (tested in the
MonarchE trial: NCT03155997), are eagerly anticipated.
Ongoing neoadjuvant trials such as the iSPY 2 study
(NCT01042379) involving multiple targeted agents, as
well as immunotherapies, might pave the way for the
use of tailored, risk-stratified approaches to adjuvant
therapy in the future. In this regard, the ultimate goal of
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Reviews
Diagnosis and
primary surgery
0–5 years of
endocrine therapy*
Clinically detectable
breast cancer
No response
owing to
resistance
Treated primary
breast cancer
Distant recurrence
(beyond 5 years)
Women with early
(0–5 years) or late
(>5 years) distant
recurrence
e
Micrometastases
50% of women with
micrometastases
Early distant
recurrence
Early
acquired g
resistance
d
b
f
40%
Partial
response
dormancy
k Exit
before 5 years
h
l
Enter
dormancy
Exit
dormancy
5 years
Micrometastases
Dormant
(distant diseasefree at 5 years)
i Maintain
dormancy
c
Early ER+
breast
cancer
Late distant
recurrence
50% of women with residual
Women with no
distant recurrence
a
60%
Complete
response
j
Cured
Cured
Dormant
Long-term
dormant
Cure and long-term dormancy are clinically indistinguishable
Fig. 1 | Outcomes of women with oestrogen receptor-positive breast cancer. Out of ~46,000 women diagnosed with
oestrogen receptor (ER)-positive (ER+) breast cancer annually in the UK, ~60% will be cured with surgery alone (part a), and
~40% will have residual micrometastatic disease after surgery (part b). The majority of these women will be treated with
endocrine therapy and might subsequently have a complete response (part c), no response (part d), which can lead to
metastatic outgrowth (part e) within a short period of time, or a partial response (part f). A partial response would be
associated with the presence of residual micrometastatic disease, which would either acquire resistance leading to early
recurrence (part g) or enter into a dormant state (part h). Dormant micrometastatic disease (part i) can be maintained,
a process that can continue beyond 5 years (part j), or exit from dormancy can occur within 5 years (part k) or beyond
5 years (part l). The percentages given after 5 years are for the population of women with micrometastatic disease after
surgery and not the overall population. *Sometimes preceded by adjuvant radiotherapy and/or chemotherapy.
clinical research in this setting is to identify biomarkers
to predict what the best tailored treatment is for each
individual patient.
Molecular and cellular mechanisms
Numerous factors can influence the emergence of late
recurrence (Fig. 2). The potentially long period that
precedes distant recurrence in patients with ER+ breast
cancer is often referred to as a period of latency or
tumour dormancy. Preclinical research into tumour
dormancy is currently a highly active area (reviewed previously17,18). In this section, we do not discuss molecular
298 | MAY 2019 | volume 16
mechanisms in detail but rather present the main principles underlying tumour dormancy with a focus on
evidence derived from preclinical models of ER+ breast
cancer and from translational studies with samples from
patients with ER+ breast cancer.
Mechanisms underlying dormancy
The term dormancy sometimes refers to reversible cellular quiescence and, in other cases, to tumour mass
dormancy19–21 (Fig. 3). In the former state, the concept is
that individual cells with metastatic potential are maintained in a state of cell cycle arrest characterized by a
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Table 1 | Randomized trials involving extended endocrine therapy
Study (dates
recruited, n and
median follow-up
duration
(months))
Intervention
(first-line therapy;
investigational arm
versus control arm)
Absolute benefita
HR (95% CI)
for disease
recurrence in the
investigational
arm
Toxicities in investigational versus
control and/or placebo armsb
NSABP-B14
(1988–1994, 1,172
and 81)
5 years tamoxifen;
5 years tamoxifen
versus placebo
4% 7-year DFS benefit in
placebo arm (P = 0.03) and 3%
7-year OS benefit in placebo
arm (P = 0.07)
1.4 (0.9–2.2)
• Grade 3–4 AEs 5% versus 3%95
• Endometrial cancer incidence
1.4% versus 0.7%8
• Hot flushes 64% versus 48%95
• Venous thromboembolism
1.4% versus 0.2%95
ATLAS (1996–2005,
6,846 (ER+) and
91.2c)
5 years tamoxifen;
5 years tamoxifen
versus no treatment
extension
3.7% 10-year recurrence
benefit for extended
endocrine therapy (P = 0.002)
and 2.8% 10-year breast
cancer-specific survival
benefit for extended
endocrine therapy (P = 0.01)
0.84 (0.76–0.94)
• Endometrial cancer incidence
116 versus 63 patients; P = 0.0002
• Pulmonary embolism 41 versus
21 patients; P = 0.01
aTToM (1991–2005,
6,953 and NA)
5 years tamoxifen;
5 years tamoxifen
versus no treatment
extension
2.6% recurrence benefit
for extended endocrine
therapy (P = 0.003) and 1.6%
OS benefit for extended
endocrine therapy (P = 0.1)
0.99 (0.86–1.15)
in years 5–6, 0.84
(0.73–0.95) in
years 7–9 and 0.75
(0.66–0.86) in year
10 or after
Endometrial cancer incidence
102 versus 45 patients; P < 0.0001
10
NSABP-B33
(2001–2003, 1,598
and 30)d
5 years tamoxifen;
5 years exemestane
versus placebo
2% 4-year DFS benefit for
extended endocrine therapy
(P = 0.07) and 2% 4-year
RFS benefit for extended
endocrine therapy (P = 0.004)
0.68 (NA)
• Grade 3 AEs 9% versus 6%; P = 0.03
• Bone fractures 28 versus 20 patients;
P = 0.33
12
MA.17 (1998–2002,
5,187 and 30)d
4.5–6.0 years
tamoxifen; 5 years
letrozole versus
placebo
4.6% 4-year DFS benefit for
extended endocrine therapy
(P < 0.001) and 0.4% 4-year
OS benefit for extended
endocrine therapy (P = 0.3)
0.58 (0.45–0.76)
• Hot flushes 58% versus 54%;
P = 0.003
• Arthralgia 25% versus 21%; P < 0.001
• Alopecia 5% versus 3%; P = 0.01
• Osteoporosis 8.1% versus 6.0%;
P = 0.03
• Bone fractures 5.3% versus 4.6%;
P = 0.25
11
ABCSG 6a
(1996–2001, 856
and 62)
5 years
tamoxifen ± aromatase
inhibitors in first
2 years; 3 years
anastrozole versus no
further treatment
4.7% 6-year RFS benefit for
extended endocrine therapy
(P = 0.031) and 1.4% 6-year
OS benefit for extended
endocrine therapy (P = 0.57)
0.62 (0.40–0.96)
• Hot flushes 39.0% versus 22.4%;
P < 0.001
• Fatigue 10.6% versus 4.3%; P < 0.001
• Joint pain 24.5% versus 18.3%;
P = 0.009
• Hair loss 9.0% versus 2.1%; P < 0.001
96
NSABP-B42
(2006–2010, 3,923
and 83)
5 years any endocrine
therapy; 5 years
letrozole versus
placebo
3.4% 7-year DFS benefit for
extended endocrine therapy
(P = 0.048) and 0.5% 7-year OS
benefit for placebo (P = 0.22)
0.85 (0.73–0.99)
Bone fractures 91 versus 72 patients;
P = 0.27
97
MA.17 R
(2004–2009, 1,918
and 75)
5 years aromatase
inhibitors ± prior
tamoxifen; 5 years
letrozole versus
placebo
4% 5-year DFS benefit for
extended endocrine therapy
(P = 0.01) and 1% 5-year
OS benefit for extended
endocrine therapy (P = 0.83)
0.66 (0.48–0.91)
• Bone pain 18% versus 14%; P = 0.01
• New-onset osteoporosis 11% versus
6%; P < 0.001
• Bone fractures 14% versus 9%;
P = 0.001
13
DATA (2006–2009,
1,860 and 50)
2–3 years tamoxifen;
6 years anastrozole
versus 3 years
anastrozole
3.7% 5-year DFS benefit for
extended endocrine therapy
(P = 0.06) and 0.4% 5-year
OS benefit for extended
endocrine therapy (P = 0.6)
0.79 (0.62–1.02)
• Arthralgia and/or myalgia 58%
versus 53%
• Osteopenia and/or osteoporosis
21% versus 16%
14
IDEAL (2007–2011,
1,824 and 79)
5 years any endocrine
therapy; 5.0 years
anastrozole versus 2.5
years anastrozole
1.4% DFS benefit for 5.0 years
(P = 0.49) and 0.8% OS benefit
for 2.5 years (P = 0.79)
0.92 (0.74–1.16)
• Overall grade 3–4 AEs 8.8% versus
10.0%; P = 0.43
• Arthralgia 14.7% versus 13.2%
• Hot flushes 13.1% versus 10.5%
• Osteoporosis 12.7% versus 7.5%
• Bone fractures 5.0% versus 2.8%
• Fatigue 9.7% versus 7.5%
15
Refs
8,95
9
AE, adverse event; DFS, disease-free survival; ER+, oestrogen receptor-positive; NA , not available; OS, overall survival; RFS, recurrence-free survival. aFirst result
provided is the primary end point of the study ; time shown is time from randomization. bToxicities of all grades have been reported when data were available.
c
Mean. dRecruitment ceased at 30 months from start of recruitment, and crossover to experimental arm was allowed. dStudy ceased at first interim analysis at
62 months from start of recruitment, and crossover to experimental arm was allowed.
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major reduction or complete absence of proliferation,
whereas tumour mass dormancy is conceptualized as an
equilibrium between a proliferating cellular population
and another population with a higher cellular death rate.
Both types of dormancy are likely to coexist, with each
one doing so as part of the same biological continuum
(Fig. 3). However, much of the evidence supporting these
mechanisms is preclinical; further translational studies
linking these mechanisms to patients with ER+ breast
cancer are needed.
The study of the mechanisms underlying both
types of tumour dormancy is hampered by difficulties
in developing cell lines and mouse xenograft models
that accurately reflect the long latency period that can
precede late-recurring ER+ breast cancer and by the
length of time needed to reach the end point in these
studies. Reference to studies involving tumour types
other than breast cancer, therefore, are included in this
Review. Another feature that has not been fully reproduced yet in experimental breast cancer models — and is
particularly relevant to ER+ breast cancer — is the effect
of oestrogen deprivation imposed by adjuvant endocrine
treatment. The differential response to adjuvant endocrine therapy will be a key determinant in the behaviour of a micrometastasis, which in some patients will be
fully ablated and in others will respond but then relapse
with a variable duration of latency in between (Fig. 2).
One particularly relevant xenograft study, however, has
highlighted the unique behaviour of ER+ micrometastases22. In this study, the authors developed ovariectomized mouse models in which injected ER+ tumour cells
seemed to be dormant for several weeks until stimulation with exogenous estrogen or progesterone triggered
the outgrowth of macrometastases. This behaviour contrasted to that observed with ER− tumour cells, which
developed metastases very quickly with no reliance on
hormone stimulation. The ER+ micrometastases showed
a low level of proliferation as measured by Ki67, thereby
suggesting true cellular quiescence. These findings could
reflect the emergence from dormancy seen in some
patients upon cessation of endocrine therapy.
The mechanisms that underlie both types of dormancy involve complex interactions between tumour
cells and their microenvironment23–26. Other key components are cancer stem cells27, the tumour vasculature28
and the host immune system29–31. The immune system
can both maintain and promote exit from tumour dormancy. Data from translational studies have revealed
that lymphocytic infiltration into ER+ breast tumours
from patients who received endocrine therapy was
associated with a poor antiproliferative response to neoadjuvant aromatase inhibitors29, in contrast to observations from studies involving patients with ER− tumours
treated with chemotherapy30. The spatial distribution,
and not merely the abundance, of tumour-infiltrating
lymphocytes has prognostic relevance in ER+ breast cancer and could be useful in defining patients with a higher
risk of late recurrence31.
The ability of a tumour to develop its own blood supply is fundamental to its growth and has been widely
investigated. In a mouse model developed to study
breast cancer dormancy, a similar balance between the
300 | MAY 2019 | volume 16
levels of the proliferation marker Ki67 and apoptotic
activity was found in both angiogenic and nonangiogenic tumours, suggesting that suppression of angiogenesis during dormancy is not always associated with
cellular quiescence28. However, in another preclinical
study, a gene expression signature for dormancy, which
was found to be more highly expressed in ER+ versus
ER− cell lines, was enriched with genes that downregulate angiogenesis and has been associated with the
maintenance of a quiescent phenotype in ER+ breast
cancer-derived cell lines32.
Exit from dormancy is an urgent research challenge,
particularly because therapies based on preventing this
process might be more feasible than those aimed at
eradicating dormant cells. Again, preclinical evidence
strongly implicates tumour microenvironment-mediated
signalling as a facilitator of exit from dormancy25,26,33, in
tandem with changes in immunosurveillance34 and the
re-emergence of highly tumorigenic cancer stem cells35
(Fig. 3). Despite the preclinical evidence pertaining to
the molecular mechanisms associated with dormancy,
to our knowledge, limited preclinical and translational
studies have been conducted to determine the specific
changes in microenvironmental factors that can trigger
the exit of breast cancer cells from dormancy. A combination of the ongoing acquisition of mutations and other
environmental factors (such as physiological stress and
ageing) is likely to tip the balance towards exit from dormancy over time. For example, haematopoietic stem cells
might be released from quiescence into proliferation by
conditions simulating those associated with inflammation or chronic blood loss36. Certain chronic conditions,
which might be directly related to tumour progression,
or events associated with high levels of physiological
stress might lead to the awakening of tumour cells from
dormancy; however, robust experimental data are not
available.
Therapeutic targets of dormancy
Dormant cells are generally considered to be resistant to
cytotoxic chemotherapy because, in most cases, efficacy
is dependent on malignant cells actively going through
the cell cycle37. Therefore, therapeutic agents targeting
different elements in the multiple signalling pathways
that enable cells or cell clusters to enter and maintain
a dormant state have become a focus of drug development strategies aimed at perpetuating that state38–40. The
development of most of these potential treatments is at
the preclinical stage. While the level of angiogenesis
seems certain to have a role in both maintaining and
exiting dormancy, trials of adjuvant and neoadjuvant
bevacizumab have, on the whole, failed to show conclusive evidence of benefit in patients with breast cancer41.
An exploratory sub-analysis revealed that bevacizumab
had a greater effect in ER+ patients, but tests for interaction between hormone receptor positivity and effect
of bevacizumab on DFS and OS were not significant.
This lack of data does not necessarily negate the importance of the development of the vasculature but, rather,
might reflect the ability of bevacizumab to target this
mechanism. Nonetheless, endocrine therapy, as is discussed further, is currently the mainstay of eliminating,
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Disease presentation
and surgery
Endocrine
therapy
Chemotherapy
Level of
detection
5 years
a
Micrometastases 4
7
5i
5ii
6
8
9
Dormancy
2
1
2
Ablation
3
b
Level of
detection
Micrometastases
7
5i
1
c
5ii
6
8
9
Dormancy
Ablation
Level of
detection
Micrometastases
Dormancy
Ablation
Fig. 2 | Potential effects of a 5-year course of adjuvant endocrine therapy with or without chemotherapy on the
natural history of subclinical micrometastatic disease. In this diagram, the slopes of the blue lines represent the growth
rate of the metastases. a | Behaviour of a large-sized micrometastasis. Different outcomes can occur: cure owing to
complete response to chemotherapy (1) or endocrine therapy (3), partial response to chemotherapy and endocrine
therapy (2), innate resistance to endocrine therapy (4), stable dormant disease followed by early-stage (5i) or late-stage
(5ii) acquired therapeutic resistance, beginning of disease recurrence with subsequent disease regression as a withdrawal
response to adjuvant tamoxifen treatment (6), which would lead to disease to become dormant or be fully ablated,
emergence of distant disease upon cessation of endocrine therapy (7) or at a later stage of follow-up monitoring (8), or
establishment of stable, long-term dormancy (9). b | Behaviour of a small-sized micrometastatic lesion, including large
lesions that have been reduced in size by adjuvant therapy. The outcomes in this situation have been described in panel
a, but the emergence of recurrent disease is delayed in comparison with that scenario because of the smaller size of
the metastatic lesions at the time of surgery. c | Multiple factors leading to the outgrowth of metastatic lesions and
overt late-stage recurrence. In the example in the red dotted circle, six recurrent lesions emerge at a similar time
(~7 years after surgery). The dotted blue and orange lines denote a patient in which a withdrawal response might lead to
tumour ablation.
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volume 16 | MAY 2019 | 301
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Exit from
dormancy
Macrometastases
g
Micrometastasis with
two different, equal
size cellular clones
b
Micrometastasis
with selection of
orange clone
c
Emergence from
quiescence
• Angiogenic switch
• Microenvironment
signalling
• Changes in immune
system
Cell proliferation
Balanced proliferation
and cell death
• Microenviroment
signalling
• Immune equilibrium
• Stem cell and/or
luminal differentiation
equilibrium
a
e
Cellular quiescence
• ↓ Angiogenesis
• Dormancy-permissive
microenvironment
signals
f
Emergence from
balanced proliferation
and cell death
• Acquisition of mutations
• Dominance of
tumorigenic stem cells
• Immune system changes
• Other host changes
Cell death
Cell death
d
Maintained dormancy
Fig. 3 | Coexistence of two modes of dormancy: cellular quiescence and balanced proliferation and cell death.
Quiescence is represented herein by a micrometastatic lesion with two clonal populations that are not actively going
through the cell cycle (with no cellular proliferation or death). This lesion can remain in this state, switch to balanced
proliferation and cell death (part a) or exit dormancy (part b). In balanced proliferation and cell death, equivalent low levels
of cellular proliferation (part c) and cell death (part d) exist in the cell populations of the lesion, and no selection between
the two clonal populations occurs. The lesion can remain in this state or switch to cellular quiescence (part e) or exit
dormancy (part f), which can be followed by the emergence of a dominant clone that is likely to be resistant to endocrine
therapy (part g).
or at least controlling, micrometastatic, proliferating ER+
tumour cells.
Overall, much remains to be discovered within
the scientific conundrum of dormancy in ER+ breast
cancer. Newly developed organoid-based models and
patient-derived xenografts might enable better reproduction of the biology of late recurrence to further
advance the study of this area. Future studies should be
aimed at elucidating the specific molecular triggers that
bring about escape from dormancy.
Predicting risk of late recurrence
Clinicopathological predictors
Individual clinical predictors of recurrence, often termed
classical variables, have been extensively investigated.
Classical variables include tumour size, tumour grade,
Ki67 index, patient age and degree of lymph node
involvement. The burden of micrometastatic disease
and its proliferation rate likely affect the risk and timing
of disease recurrence (Fig. 2); thus, clinical variables that
inform on disease burden and proliferation rate are likely
to be good predictors of the risk of late recurrence. The
only independent clinical variable consistently shown to
be associated with the risk of late recurrence is lymph
node burden1,42,43. Tumour size has also been shown
302 | MAY 2019 | volume 16
to be independently associated with late recurrence
in some studies43, including a meta-analysis involving
>60,000 women who were alive and free from distant
recurrence at 5 years after diagnosis2. One of the most
notable findings of the latter study was that the cumulative risk of recurrence among women with the lowest
stage tumours (T1N0) was as high as 13%.
Clinicopathological data such as tumour size, tumour
grade and lymph node burden have been incorporated
into several prognostic models, such as the Nottingham
Prognostic Index and NHS Predict, which are both
designed to be used at the time of diagnosis to guide
decisions on adjuvant endocrine therapy and/or chemotherapy. These methods are attractive because they represent an accessible, immediate and cost-free approach
to risk prognostication that can be used in most routine
clinical settings worldwide. The clinical treatment score
at 5 years (CTS5), reported in 2018, has been specifically
developed to predict risk of late recurrence in women
who have not had distant disease recurrence 5 years after
diagnosis44. This score was based on the original clinical treatment score at diagnosis (termed CTS), which
itself was a model of clinical variables developed to be
used alongside the immunohistochemistry 4 (IHC4)45.
In the validation data set for CTS5, an increasing score
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had a positive correlation with risk of late recurrence.
Additionally, the CTS5 divided the study cohort into
three risk groups, the lowest of which had a 3.6% risk
of distant recurrence at years 5–10. Consistent with the
findings of previous studies1,42,43, having a high burden
of lymph node metastases was a strong predictor of late
recurrence, hence its heavy weighting in the CTS5, confirming the prognostic relevance of this factor in the late
disease setting.
Individual molecular biomarkers
Very limited evidence exists on the association between
the molecular mechanisms proposed to underlie tumour
dormancy and the likelihood of late recurrence, but data
are available on individual biomarkers and gene signatures that should be considered both to understand the
biology of late recurrence and, potentially, as prognostic
tools. Several studies have been conducted retrospectively in cohorts of patients with ER+ breast cancer, some
of whom received endocrine therapy for 5 years46–51.
A study by Bianchini et al. has been particularly insightful in its examination of oestrogen signalling-related
genes that might differentiate early recurrence from late
recurrence46. In this study, specimens of early-stage ER+
breast cancers derived from patients treated with tamoxi­
fen for 5 years were classified according to the average
expression levels of 12 genes encoding mitotic kinases
and four ER-associated genes analysed in the gene signature Oncotype DX (ESR1, PGR, SCUBE2 and BCL2).
Among patients with a high mitotic kinase-related score,
a high ER-associated gene expression score was indicative of improved DFS 0–5 years after diagnosis but of
worse DFS 5–10 years after diagnosis, a result that was
consistent across patients regardless of whether they had
lymph node involvement.
A similar analysis of genes and gene modules
from the Oncotype DX signature in patients from the
TransATAC study47 revealed that high expression of
the same ER-related genes was indicative of a favourable
prognosis in years 0–5 but not in years 5–10 — ESR1
and SCUBE2 were the genes whose prognostic relevance changed the most in this regard47. Furthermore,
high levels of PGR expression, a favourable prognostic
feature in the early recurrence setting, lost prognostic
value in the late recurrence setting, a finding that was
also reported in the EBCTCG meta-analysis2, in which
Ki67 retained a moderate level of prognostic relevance
for late recurrence.
SCUBE2 encodes a tumour suppressor protein
involved in the signalling processes that reverse
epithelial-to-mesenchymal transition (EMT), which
leads to reduced levels of tumour cell invasiveness48. The
potential of SCUBE2 as a biomarker has been explored in
a study of 156 samples from patients with breast cancer
in which positive SCUBE2 expression was independently
associated with an improved DFS hazard ratio for distant recurrence (0.26 (95% CI 0.13–0.49); P = <0.0001);
however, only 58% of the tumours analysed were ER+,
and the median follow-up duration was 44 months49.
In agreement with the results of TransATAC47, in a
translational study of 750 patients with high-risk hormone receptor-positive breast cancer receiving adjuvant
NAtuRe Reviews | ClInIcAl Oncology
chemotherapy50, the levels of expression of SCUBE2 were
almost twofold higher in the subgroup of patients with a
reduced risk of recurrence than in those in the high-risk
group at 0–5 years after diagnosis, a result that was independently validated in samples from the METABRIC
study50. These results, however, are not informative of
the risk of late recurrence because the median follow-up
duration of this study was 76 months. Taken together,
the results of these studies of individual molecular biomarkers46,47 suggest that adjuvant endocrine therapy
maintains tumour dormancy in a population of residual cancer cells in a subgroup of women with primary
breast tumours with high levels of ER or ER-related gene
expression. We estimate this to be ~40–50% of those
women who are free from disease 5 years after diagnosis. On cessation of endocrine therapy, the dormant
cell population would then proliferate in response to
resumed oestrogen signalling, resulting in late recurrence. This model is not entirely concordant with the
results of a retrospective study assessing the expression
of genes from the EndoPredict signature52 in samples
from the ABCSG 6 and ABCSG 8 trials51, in which
patients with hormone receptor-positive breast cancer
received 5 years of endocrine therapy. An increased
expression of proliferation genes was associated with a
significantly increased risk of recurrence in years 0–5
(P < 0.001) but not in years 5–10 (ref.51). In contrast with
the observations of Bianchini et al.46 and data from the
TransATAC study47, the expression of genes related to ER
signalling was not prognostic of recurrence in years 0–5
but, similar to the other two studies46,47, was significantly
associated with an increased risk of recurrence in years
5–10 (P < 0.001). An explanation for these differences
could be that the oestrogen-related genes in Oncotype
DX and EndoPredict have different biological relevance.
Molecular profiles: IHC4
The identification of ER, progesterone receptor and
HER2 (also known as ERBB2) as prognostic biomarkers in patients with breast cancer has transformed the
management of patients in both early and metastatic disease settings. These biomarkers and Ki67, all evaluated
using immunohistochemistry, have been integrated in
the IHC4 score, which has been validated as a prognostic
model for risk of recurrence at 0–10 years45. Most of the
information captured in IHC4 has prognostic value in
the early recurrence setting, but in the late recurrence
setting, it does not have prognostic value superior to
that derived from standard clinical variables43,53. This
difference can be explained by the strong weight that
the ER component has in the IHC4 algorithm, which has
been validated in the early recurrence setting; the shift in
prognostic importance of ER-related genes after 5 years
has already been discussed for Oncotype DX.
Molecular profiles
Several molecular tests enable quantification of the
levels of the RNAs from multiple genes in a primary
tumour sample and have shown prognostic value for
the evaluation of risk of distant recurrence in years
0–10 after diagnosis. Promising results have also
been obtained when several of these gene signatures
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Table 2 | Commercially available molecular assays for risk prognostication in patients with breast cancer tested for late recurrence
Refs
Patient characteristics (number of
patients alive and with no distant disease
recurrence after 5 years of endocrine
therapy)
Absolute risk (% (95% CI)) of
distant recurrence for patients in
lowest-risk group
Percentage
of patients in
lowest-risk group
TransATAC (5–10)
• 535 LN− and 154 LN+ (separate analysis)
• Postmenopausal
• No prior chemotherapy
LN− 4.8 (2.9–7.9) and LN+ 17.9 (11.5–27.3)
LN− 65.6 and LN+ 61.0
58
NSABP-B28 (5–10)
• 832
• 48% <50 years of age (menopausal status
not specified; data correct at the time of
randomization and not at 5 years)
• 100% LN+
• 100% received chemotherapy
11.7 (8.6–15.7)
40.5
59
NSABP-B14 (5–15)
• 564
• 29% <50 years of age (menopausal status
not specified; data correct at the time of
randomization and not at 5 years)
• 100% LN−
• No prior chemotherapy
• 4.8 (2.8–7.9) in years 5–10
• 6.7 (4.3–10.4) in years 5–15
54.8
59
TransATAC (5–10)
• 535 LN− and 154 LN+ (separate analysis)
• Postmenopausal
• No prior chemotherapy
LN− 1.4 (0.5–3.8) and LN+ 0 (n = 15; no
events)
LN− 54.6 and LN+ 9.7
58
ABCSG 8 (5–15)
• 1,246
• Postmenopausal
• 74% LN−
• No prior chemotherapy
Overall 2.4 (1.1–5.3), LN− 2.5 (1.1–5.4)
and LN+ 0 (n = 12; no events)
36.9
69
TransATAC and ABCSG
8 (5–10)
• 2,137
• Postmenopausal
• 74% LN−
• No prior chemotherapy
2.4 (1.6–3.5)
55.4
62
TransATAC (5–10)
• 535 LN− and 154 LN+ (separate analysis)
• Postmenopausal
• No prior chemotherapy
LN− 4.3 (2.6–7.1) and LN+ 3.3 (0.5–21.4)
LN− 73.5 and LN+ 26.0
58
ABCSG 6 and ABCSG 8
(5–10)
• 998
• 71% LN−
• Postmenopausal
• No prior chemotherapy
1.8 (0.2–3.5)
64.3
51
TransATAC (5–10)
• 535 LN− and 154 LN+ (separate analysis)
• Postmenopausal
• No prior chemotherapy
LN− 2.6 (1.3–5.0) and LN+ 9.5 (8.3–23.9)
LN− 63.6 and LN+ 54.6
58
Stockholm TAM (5–10)
• 285
• 100% LN−
• Postmenopausal
• No prior chemotherapy
2.8 (0.3–5.2)
65
66
Multi-institutional
cohort (5–10)
• 312
• 100% LN−
• 70% postmenopausal
• 32% received chemotherapyb
2.5 (0–5.0)
58
66
NA
57
53
3.0% (2.4–3.6)
42.7
Cohort in which
test was used and
follow-up duration
after diagnosis (years)a
Oncotype DX
PAM50
EPClin
Breast Cancer Index
Immunohistochemistry 4 (IHC4) score
TransATAC (5–10)
• 596
• 100% postmenopausal
• 100% LN−
• No prior chemotherapy
Clinical treatment score at 5 years (CTS5)
ATAC and BIG 1-98
(5–10)
• 11,446
• 64% LN−
• 100% postmenopausal
• 21.8% received chemotherapy
44,98
LN−, patients without lymph node involvement; LN+, patients with lymph node involvement; NA , not available. aIn all cohorts, distant recurrence-free survival was
the end point. bData correct at the time of randomization and not at 5 years.
304 | MAY 2019 | volume 16
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have been used to estimate the risk of late recurrence
(Table 2). MammaPrint, an important signature54, is not
discussed herein because it has not been evaluated in the
setting of late recurrence.
Oncotype DX recurrence score. The Oncotype DX recurrence score is a purely molecular model that is evaluated
using reverse transcription PCR (RT-PCR) assays and
incorporates 21 genes (including 6 housekeeping genes)
related to proliferation, survival, invasion and oestrogen signalling55. Oncotype DX has shown prognostic
value for the risk of recurrence 0–10 years after diagnosis55 and has been argued to enable the prediction
of benefit from adjuvant chemotherapy56,57. Regarding
late recurrence, however, Oncotype DX showed poor
performance in several retrospective studies of the
TransATAC patients43,53,58 when used to discriminate
between patients with a high and a low risk of recurrence 5 years after treatment and did not improve on
the performance of the CTS, probably owing to reasons
already discussed. Oncotype DX was reported to have
significant prognostic performance for late recurrence
(5–15 years after diagnosis) in patients who had ESR1
levels that were described as higher (HR for recurrence
2.23 (95% CI 1.11–4.47); P = 0.04), a cut-off that actually
excluded only the 10% of patients with the lowest ER
levels from the overall population59. Of note, although
the risk of distant recurrence in years 0–5 was 2.1% and
22.1% in the low-risk and high-risk groups, respectively,
the difference between groups was reduced after 5 years
(6.7% and 13.6%), consistent with the reduced separation for late recurrence seen in TransATAC (where the
difference between high and low was 5.4%)43.
PAM50. The PAM50 score combines the expression levels of 50 genes and tumour size, which are used to define
the intrinsic subtypes of breast cancer, and information
from a set of proliferation-related genes for prognostic
purposes60. PAM50 has prognostic value for the prediction of recurrence risk between year 0 and year 10 (ref.61),
with similar performance for the prediction of risk at
years 0–5 and 5–10 (refs43,58). The combined analysis of
the ATAC and ABCSG 8 trial populations also demonstrated that PAM50 had prognostic value in the late
recurrence setting, independent of the CTS62. Of note,
the net reclassification index (a tool used to compare the
performance of one prognostic tool with another) for
the prognostic performance of PAM50 plus CTS versus
CTS alone was significant (9.3% reclassified; P < 0.001),
indicating that the combination of PAM50 and CTS
improves risk classification compared with CTS alone. In
this analysis, 24.6% of women with lymph node-positive
disease were allocated to the low-risk group, with a
5–10-year risk of recurrence of only 2.4%.
EndoPredict. EndoPredict is a 12-gene expression panel
that is combined with clinical parameters to generate an
EPClin score52. EPClin has good prognostic value for the
prediction of disease recurrence 0–10 years after diagnosis52,63 and of late recurrence in a combined cohort from
the ABCSG 6 and ABCSG 8 studies51. In samples from
the TransATAC study, EPClin was found to have a higher
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prognostic value for late recurrence than EndoPredict
alone (likelihood ratio for distant recurrence in years
5–10 of 59.3 versus 23.6; P < 0.001 (ref.63)).
Breast Cancer Index. The Breast Cancer Index (BCI)
is a molecular score that incorporates the ratio of
HOXB13:IL17BR levels and a proliferation-related
five-gene module referred to as Molecular Grade
Index64. When tested in the Stockholm TAM data set65,
a heterogeneous cohort (in terms of breast cancer risk)
of 1,374 postmenopausal women treated with tamoxifen,
BCI had independent prognostic value for recurrence
beyond 5 years66. In TransATAC53, BCI had independent
prognostic value for late recurrence in women with no
lymph node involvement. In an analysis of the prognostic ability of BCI in a cohort of 547 patients with T1N0
ER+ disease, ~30% of the patients were classified as having a high risk of recurrence with a significantly reduced
DFS at 5–15 years after diagnosis compared with those
who were deemed to have a low risk according to BCI67.
Uniquely among breast cancer molecular profiles, the
predictive value of the HOXB13:IL17BR ratio has been
tested for its ability to predict responses to extended
letrozole therapy. In patients involved in the MA.17
study11, a high ratio in the placebo group was independently associated with a significantly increased risk
of recurrence (OR 2.24 (95% CI 1.09–4.61); P = 0.03). In
the same study, patients with a high HOXB13:IL17BR
ratio derived a significantly greater recurrence-free
survival benefit from extended letrozole than those
with a low ratio (OR for distant recurrence in high
HOXB13:IL17BR ratio group 0.35 (95% CI 0.16–0.75);
P = 0.007)68. Thus, the BCI not only enabled the identification of patients with a higher risk of late disease recurrence, but it also enabled those who could benefit from
extending the duration of adjuvant endocrine treatment to be identified. Of note, the study of BCI performance in the MA.17 cohort was a small, retrospective,
case–control comparison that requires validation in an
independent, larger data set.
Comparison of molecular profiling tools. A comparison of several molecular prognostic assays within
TransATAC showed the additional prognostic value
of BCI, EPClin and, in particular, PAM50 in the late
recurrence setting above that of CTS alone58. By contrast, Oncotype DX and IHC4 did not improve on the
prognostic performance of CTS in this setting. When
PAM50, BCI and EPClin were each individually used to
stratify the patients with lymph node-negative disease
into risk groups, the lowest-risk group included at least
50% of patients with no lymph node involvement, who
have been defined as having a <5% risk of late recurrence
in years 5–10 after diagnosis.
Taken together, despite not being developed specifically for the evaluation of the risk of late recurrence,
PAM50, EPClin and BCI all have good prognostic value
in this setting. All three models enable clinically valid risk
groups to be defined, the lowest of which includes women
for whom extended endocrine therapy might not be warranted. Of note, the existence of these molecular models
challenges the concept that single clinicopathological
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variables, such as tumour size and lymph node involvement, can be used for recurrence prognostication —
findings from several studies mentioned above showed
that women with lymph node-positive disease can be
deemed at low risk and vice versa. One common thread
running through the patient cohorts used in the validation studies mentioned above is that the large majority
of patients are postmenopausal women with low-risk
baseline features. While these results are highly informative, the patients included probably do not completely
reflect the heterogeneous patient populations seen in routine
clinical settings. In subgroup analyses of data from many
of the translational studies58,62,69, the prognostic value of
the genomic tests was weaker for women with lymph
node-positive disease, a feature that might reflect the
low patient and event numbers analysed or lymph node
burden having a dominant prognostic effect over that
of other variables. Despite this limitation, BCI, EPClin
and PAM50 remain good tools for risk stratification in
patients with lymph node involvement58. More data are
needed from premenopausal women and those at higher
risk of recurrence who were treated with chemotherapy,
who are probably the patient populations most likely to
be offered extended endocrine therapy on the basis of
molecular prognostic models.
Late recurrence and dormancy signatures. Noncommercial signatures specific to late recurrence and
dormancy have been developed and tested in addition
to the commercially available gene expression models
described above. A signature comprising the expression
of 49 genes relating to tumour cell quiescence and failure of angiogenesis has been derived from experimental
models and tested in a combined set of ER+ tumours32.
Those with higher dormancy scores were associated with
improved metastasis-free survival with a 2.1-fold hazard ratio compared to those with low dormancy scores.
Another signature that was found to be associated with
late recurrence contained epithelial and stromal genes
involved in EMT and with expression levels that were
directly related to epithelial–mesenchymal plasticity in
primary tumour cells70. The stromal component alone
had a strongly significant association with time to recurrence, thus reflecting the importance of the surrounding
microenvironment to tumour dormancy. How these
two signatures perform in comparison with the established commercial signatures remains to be established.
However, in a large study of time-dependent gene expression signatures for the prediction of late recurrence, a
specific 5–10-year signature did not improve risk estimation above that provided by a 0–10-year model.
The authors conclude that further specific late recurrence signatures are unlikely to improve on the performance of the existing risk prediction models developed
to study recurrence 0–10 years after diagnosis71.
Mutations and copy number alterations
DNA mutations in the form of point mutations, copy
number alterations (CNAs; which include amplifications or deletions) and translocations are common in
all tumour types and accumulate over time. The incidence of these alterations depends on the proliferative
306 | MAY 2019 | volume 16
activity of cancer cells, and therefore, in a dormant but
not fully quiescent tumour, they are likely a determinant
of late recurrence risk. When DNA alterations affect a
driver gene, the situation can lead to the emergence of
a dominant clone. Such an alteration could facilitate the
conversion of a small, dormant micrometastatic deposit
into an overt metastatic lesion and therefore lead to late
recurrence. A very limited amount of data from direct
observations support this hypothesis, probably because
a small number of studies have undertaken comprehensive, comparative sequencing of material from primary
breast tumours and their associated metastases. A study
by Yates et al.72 stands out in this regard, even though the
researchers did not distinguish between early and late
recurrence. Consistent with the findings of other studies73, they reported that the most common mutations
in early-stage ER+ breast cancer affected PIK3CA and
TP53; mutations in many other genes were described but
generally with an incidence <5%73. Overall, the genomic
landscape of metastases was found to be closely related
to that of the primary tumour because the authors found
that clonal mutations tended to persist in the metastases
in patients with relapsed disease — suggesting that therapeutic decisions made on the basis of mutational signatures in the primary tumour can be extrapolated in the
context of metastatic disease. In addition to this observation, however, the authors reported that metachronous
metastases had, on average, mutations in two-thirds
more genes (including driver genes) than the primary
tumour, with a higher rate of mutation acquisition. This
result demonstrates that, despite similarities in clonal
mutations, heterogeneity exists in subclonal mutations
that have arisen after micrometastatic colonies have
seeded at distant sites.
Mutations in ESR1 that confer constitutive activation
of the mutated ER protein independent of ligand binding
have been detected in ~20% of tumour samples derived
from patients with metastatic ER+ breast cancer treated
with an average of two prior lines of endocrine therapy74 and in ~40% of circulating tumour DNA (ctDNA)
samples from patients with metastatic ER+ breast cancer
with disease progression on treatment with an aromatase
inhibitor75. The frequency of ESR1 mutations in a cohort
of women treated with tamoxifen with no prior aromatase
inhibitor exposure was reported as 0/22 in a retrospective
study of consecutive patients with ER+ advanced-stage
breast cancer76. This study showed that 95% patients
with ESR1 mutations had received an aromatase inhibitor as part of their treatment for metastatic disease. While
limited data exist on emergence of ESR1 mutations during or after adjuvant endocrine treatment, the evidence
suggests that some late recurrences might be driven by
an ESR1 mutation in patients treated with aromatase
inhibitors but not with tamoxifen. However, with treatment discontinuation at 5 years, the loss of the selective
pressure derived from oestrogen deprivation could lead
to clones harbouring ESR1 mutations no longer having
an advantage. A retrospective study involving 42 women
treated for at least 2 years with aromatase inhibitors in
the adjuvant setting and who subsequently had disease
recurrence showed that only two patients had ESR1
mutations that were detectable in plasma ctDNA at the
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time of recurrence77. Interestingly, those two recurrences
occurred at 20 months and 48 months after discontinuation of endocrine therapy that had been maintained
for at least 5 years indicating that, in those two patients,
the mutated resistant clone was able to survive for many
months and eventually propagate.
Most genetic alterations driving the progression of
breast cancer appear to arise from CNAs; their contribution to metastatic dissemination has been characterized
in a number of detailed studies, albeit with modest-sized
cohorts78–80. CNA in clinical samples from two studies
of ER+ breast cancer in the neoadjuvant setting were
analysed; amplification of CHKA was associated with a
poor response to neoadjuvant aromatase inhibitor therapy79. This gene was reported to drive ER-modulated cell
cycle progression, and its amplification was considered
to drive overexpression. Additionally, CNAs have been
incorporated into a molecular signature for recurrence
prognostication from time of diagnosis. Genes with both
changes in expression and copy number variation have
been incorporated into a molecular signature80. Internal
validation has demonstrated the ability of the score associated with this signature to separate the study cohort
into three distinct risk groups, the lowest of which had a
distant recurrence rate of 11% over 7 years (at a median
follow-up duration of 99 months)80. Similar to the role of
point mutations, while the acquisition of CNAs can be
expected to drive early or late recurrence in some patients,
this process remains to be analysed in large-scale studies
of the molecular features of recurrent disease in relation
to time since diagnosis and the effect of treatment.
Minimal residual disease. Given the incidence and eventual mortality of ER+ breast cancer, the proportion of
women with micrometastatic or minimal residual disease after surgery is estimated at 40% (Fig. 1). Currently,
following surgery, patients are recommended to receive
adjuvant systemic endocrine therapy and/or chemotherapy purely on the basis of baseline risk factors owing to
the lack of a clinically available method for measuring
minimal residual disease (MRD). The same situation
occurs in patients who have received endocrine therapy
for 5 years, and thus, the decision to extend therapy is
based on risk prognostication using both clinical variables (such as age) and pathological variables (such
as tumour size and grade of the primary tumour). In
all types of breast cancer, the presence of disseminated
tumour cells (DTCs) within the bone marrow is associated with an approximately twofold increase in the risk
of recurrence and death81. Methods based on the measurement of circulating tumour cells (CTCs) and ctDNA
are being developed for prognostic purposes in patients
with early-stage breast cancer after promising results
were obtained in those with metastatic disease75,82,83.
Levels of CTCs have been demonstrated to be important factors for both prediction of progression-free survival (PFS) and OS at the initiation of a new treatment
in the metastatic setting and, more importantly, as part
of on-treatment monitoring83. Results from studies in
metastatic breast cancer have shown that ctDNA detection of mutant ESR1 was associated with improved PFS
with fulvestrant compared with exemestane following
NAtuRe Reviews | ClInIcAl Oncology
progression on an aromatase inhibitor75 and that early
suppression in levels of mutant PIK3CA during palbociclib treatment can predict improved PFS substantially
earlier than changes in tumour size82.
CTCs can be detected using flow cytometry with
CELLSEARCH. In patients with early-stage breast cancer, the presence of CTCs was shown to be a biomarker
of innate resistance to chemotherapy84 and was prognostic of less favourable DFS and OS outcomes up to 5 years
after diagnosis85. In a report published in 2018 (ref.86) on
the prevalence of CTCs in patients with breast cancer,
CTCs were detected at 5 years in 7% of those with ER+
disease (all of whom had received endocrine therapy)86.
Interestingly, the majority of patients (36/47) who had
detectable CTCs at 5 years had negative results at 2 years,
suggesting that the CELLSEARCH assay could be useful
for tracking re-emergence of resistant disease.
The prognostic value of CTCs for late recurrence was
analysed in a study of 353 women treated for early-stage
ER+ breast cancer who had no distant disease recurrence
after 5 years of endocrine therapy87. The study, with
results published in 2018, demonstrated that the presence of CTCs at 5 years was associated with a 13-fold
increase in the risk of recurrence (independent of clinical
co-variates) thereafter compared with patients without
detectable CTCs; the number of CTCs was directly correlated with the risk of recurrence87. While the number
of ER+ patients involved in the study was low and the
follow-up duration was <5 years, this is, to our know­
ledge, the first study providing evidence of the prognostic
value of CTCs for late recurrence in ER+ breast cancer. As
such, this study supports the feasibility of CTC detection
as a tool for monitoring women who are free from distant disease at 5 years. To further establish the prognostic
value of CTCs in late recurrence, longer follow-up durations, as well as serial measurements during treatment
with endocrine therapy and after cessation, are needed.
Over the past few years, data have emerged suggesting that ctDNA might have a similar role to CTCs
in enabling detection of MRD. The authors of a study in
the neoadjuvant setting88 reported that post-surgical
serial tracking of mutations in ctDNA had a significant
prognostic value for early recurrence with improved
lead times for detection compared with imaging-based
monitoring88. Longer follow-up durations and different
study designs are required to assess the prognostic value
of monitoring ctDNA following adjuvant treatment and
extrapolate its relevance for late recurrence.
The majority of the current evidence in this regard
comes from studies involving MRD detection following
surgery and immediately after, but it is likely to be at least
as useful for women who have reached 5 years without
distant recurrence to better distinguish between patients
who are likely to be cured and those with MRD after
5 years of therapy (Fig. 1). However, a critical link yet
to be made is that between earlier detection of MRD
and improved patient outcomes, thereby justifying
long-term, serial disease tracking, which might extend
over several decades. CTCs are detectable in the blood
>20 years following curative treatment for breast cancer89, and, given their short half-life, DTCs must exist
in an inactive state and be reactivated at a later stage
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in some women by triggers that have yet to be identified. Owing to this uncertainty, the questions of which
patients should be monitored and how to investigate
positive results must be addressed.
Clinical management of late recurrence
In an epidemiological study of >430,000 women with
varying stages of invasive and non-invasive breast cancer
diagnosed between 1973 and 2000, including >116,000
women with localized (node-negative) or regional
(node-positive) invasive ER+ disease, cause of death was
analysed90. Of those women with localized ER+ disease
who died in the follow-up period (n = 11,406), only
22% of deaths were breast cancer related. For those with
regional ER+ disease who died in the follow-up period
(n = 3,465), 56% of deaths were breast cancer related.
Overall, therefore, the majority of women who died did
so owing to causes unrelated to their breast cancer. For
those women who survive their ER+ breast cancer, survivorship extends through a long period of time during
which they face other non-breast cancer health-related
events. Therefore, clinicians must make recommendations for the prolonged management and follow-up of
their patients with a history of breast cancer. In most circumstances, the biology of late recurrence will be only
of academic interest to the clinician, but the risk of late
recurrence will be of central importance and will need to
be evaluated alongside other clinical factors when discussing long-term management with a patient. Several
key points in decision-making include the absolute risk
of late recurrence, the likelihood of risk reduction with
endocrine therapy (or another systemic therapy), the
toxicities associated with systemic therapy, the patient’s
long-term risks from continuation of endocrine therapy
(endometrial cancer, bone density and venous thrombo­
embolism risk) and personal preferences. In terms of risk
estimation, several clinical algorithms have been validated for the majority, but not all, patients. Several molecular profiling assays can also be used to stratify patients
into risk groups in relation to late recurrence. Whether
patients are stratified into meaningful groups (clinical
validity) and whether the resulting treatment changes
ultimately improve outcomes (clinical utility) need to be
established. Clinical validity has been shown for PAM50,
EPClin and BCI, as discussed above, but clinical utility
and the predictive benefit of extended endocrine therapy
on the basis of these assays are yet to be proved. Of note,
the annual risk of relapse is generally appreciable, even in
patients deemed at low risk, and therefore, the cumulative
risk can become substantial over a time span of decades.
We propose a decision matrix for the combined
use of clinical and genomic tests for risk stratification
of patients upon completion of 5 years of endocrine
therapy without distant recurrence (Fig. 4). This model
can assist patient management if used in the context of
patient–clinician conversations, taking into account the
patient’s preferences and any adverse effects of endocrine therapy that they might have experienced. Specific
cut-off values for risk are not proposed herein. Clinicians
need to estimate the likely absolute benefit from extending adjuvant endocrine therapy based on the estimates
of risk without such treatment.
308 | MAY 2019 | volume 16
When extended adjuvant therapy is deemed appropriate, aromatase inhibitors should be continued in women
who were postmenopausal at diagnosis. To our know­
ledge, no studies have specifically addressed a switch
from aromatase inhibitor-based to tamoxifen-based
therapy, but it is unlikely that this approach provides
a survival benefit; it could be recommended for some
patients owing to its different toxicity profile. Tamoxifen
should be continued in women who are premenopausal
at diagnosis and remain premenopausal 5 years after
starting treatment; those who become postmenopausal
during treatment can switch to an aromatase inhibitor
or remain on tamoxifen — again, this decision should
be driven by the patient’s preferences after considering
potential toxicities.
The importance, and the complexity, of communicating risk of recurrence to patients has markedly
increased with the advent of genomic prognostic models.
Explaining the concept of risk over long periods of time
can be particularly challenging. The use of plain language,
quoting absolute risk instead of relative risk, and the use
of pictographs are currently considered the most effective
methods of risk communication91. As data from preclinical and translational studies have shown, early and late
recurrence are, to a certain degree, different phenomena
associated with distinct risk factors; for some patients,
this difference must also be adequately explained.
A further complication in the long-term management
of breast cancer survivors is that in some health-care systems (including in the UK), they do not receive follow-up
monitoring in routine hospital-based settings but instead
via patient-led, managed self-care or open-access programmes, with rapid contact with clinical teams should
the need arise. This approach has been shown to be as
effective as more-intensive, hospital-based follow-up
monitoring in terms of DFS, OS and patient-recorded
quality of life outcomes92. These models have therefore
been enshrined in guidance in both the USA and the
UK. In these programmes, however, discussions of late
recurrence might be conducted by correspondence or
telephone, rather than in person, which carries the risk
that some women might have become disengaged from
their health-care providers.
The attitude of survivors of breast cancer to the
self-management of their long-term risk of recurrence
has not been well characterized and is likely to vary
between individuals in terms of both personal attitudes
towards the adverse events derived from long-term
treatment and psychological aspects. Patients frequently
cite endocrine therapy as a daily reminder of their
cancer that they would much rather forget about and,
therefore, committing to a further 5 years could have
important psychological as well as physical implications
but also uncertain levels of benefit. Fear of recurrence
is a well-characterized phenomenon associated with
increased anxiety, frequent medical consultations and
reduced ability to plan for the future93. In one study,
investigators reported that one-third of breast cancer
survivors overestimate their risk of recurrence by twofold, a phenomenon which is correlated with frequent
anxiety94. Grappling with the potential risks of disease
recurrence beyond 5 years could considerably increase
www.nature.com/nrclinonc
Reviews
CTS5 result
No genomic test
required (patient
unlikely to benefit
from extended
endocrine therapy)
Completed Low
clinical risk
5 years
endocrine
therapy
Borderline
Intermediate
clinical risk
Offer genomic test
for late recurrence
(e.g. PAM50, BCI or
EPClin)
Stop
endocrine
therapy
Genomic test result
Low
genomic risk
Intermediate
genomic risk
Borderline
Calculate
CTS5
High
clinical risk
Patient unlikely
to benefit and
potential toxicity
issues
Risk of late
recurrence might
be great enough
to justify extended
endocrine therapy
High
genomic risk
Risk of late
recurrence high
enough to warrant
extended endocrine
therapy
No genomic test
required; extended
endocrine therapy
should be offered
Stop
endocrine
therapy
Consider
extended
endocrine
therapy
Recommend
extended
endocrine
therapy
Recommend
extended
endocrine therapy
Fig. 4 | Decision-making aid for clinical and genomic testing. The clinical treatment score at 5 years (CTS5) should be
calculated for all women upon completion of 5 years of adjuvant endocrine therapy. For the majority of women with a low
clinical risk score, endocrine therapy can be discontinued because extended therapy is very unlikely to benefit them. For
the majority of women with a high risk of recurrence, extended endocrine therapy up to 10 years is recommended if the
toxicity profile is not unfavourable. In both situations, genomic testing is unlikely to add further prognostic information
and is not recommended. Women with an intermediate clinical risk and those at borderline low–intermediate or high–
intermediate clinical risk should receive a genomic test to enable integrated clinical–genomic stratification of their risk
of late recurrence. Following genomic testing, the following scenarios are possible: discontinuation of endocrine therapy
for patients with a low risk of recurrence or recommendation of extended endocrine therapy for up to 10 years in
patients with a high risk. Women who remain at an intermediate level of risk should discuss toxicities and personal
preferences with their clinician. Of note, the role of genomic testing as a predictor of benefit from extended endocrine
therapy remains to be established in prospective studies. BCI, Breast Cancer Index.
the incidence of comorbidities associated with physical
and/or psychological factors in some survivors of breast
cancer. Clearly, the greater awareness of the continuous
risk of late recurrence in patients with ER+ breast cancer
that has unfolded over the past few years has provided
multiple new, previously unappreciated challenges in
clinical management. We are optimistic and expect that,
in the foreseeable future, this appreciation will result in
increased basic, translational and clinical research efforts
to reduce the risk of late recurrence.
Conclusions
The late recurrence of ER+ breast cancer is a major clinical challenge. The elucidation of the mechanisms that
maintain or trigger exit from dormancy will be key in
the near future — the development of appropriate models is fundamental in this regard. Advances in the field
of RNA quantification have led to the development of
molecular prognostic models, which, coupled with
clinicopathological models, hold promise in identifying patient subgroups with distinct risk of recurrence.
Currently, perhaps the most pertinent questions are how
NAtuRe Reviews | ClInIcAl Oncology
to monitor and treat patients with a high risk of recurrence. The extension of endocrine therapy beyond 5
years has not yet shown definitive results but, in selected
subgroups, is probably associated with improved survival. Therefore, the identification of women that would
benefit from treatment (or not) is essential. The existence of improved risk prediction tools is already assisting
treatment-related decisions. Decision making might be
further improved with new tools such as the detection of
plasma ctDNA. The increasing scientific understanding
of dormancy and late recurrence is yet to affect therapeutic options but is likely to do so in the foreseeable
future. The central element in these decisions is the cancer survivor, including how she understands and wishes
to manage her risk. This concept can be approached with
patients in several ways and, ultimately, largely depends
on the individual and on the guidance she receives from
clinicians — in the era of personalized medicine, an individualized approach must permeate all aspects of clinical
management.
Published online 18 December 2018
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Acknowledgements
J.R. is a Cridlan Ross Smith Charitable Trust clinical research
fellow. The authors acknowledge support from the UK
National Institute for Health Research Royal Marsden–
Institute of Cancer Research Biomedical Research Centre.
The authors are thankful to C. Isacke and A. Ring for providing
internal review and feedback on this manuscript.
Author contributions
J.R. researched data for the article. Both authors made substantial contributions to discussions of the content, wrote the
article and reviewed and edited the manuscript before
submission.
Competing interests
The authors declare no competing interests.
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Reviewer information
Nature Reviews Clinical Oncology thanks J. Cortes, G. Viale
and the other anonymous reviewer(s) for their contribution to
the peer review of this work.
Related links
ClinicalTrials.gov database: https://clinicaltrials.gov/ct2/home
CTs5 Online Calculator: https://www.cts5-calculator.com
Nottingham Prognostic index:
http://www.pmidcalc.org/?sid=3689666&newtest=Y
NHs Predict: http://www.predict.nhs.uk/technical.html
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