Breast Cancer - 2021
Breast Cancer - 2021
Breast Cancer - 2021
Blue = Recommendations
Breast cancer
Sibylle Loibl, Philip Poortmans, Monica Morrow, Carsten Denkert, Giuseppe Curigliano
Lancet 2021; 397: 1750–69 Breast cancer is still the most common cancer worldwide. But the way breast cancer is viewed has changed drastically
Published Online since its molecular hallmarks were extensively characterised, now including immunohistochemical markers (eg, ER,
April 1, 2021 PR, HER2 [ERBB2], and proliferation marker protein Ki-67 [MKI67]), genomic markers (eg, BRCA1, BRCA2, and
https://doi.org/10.1016/
PIK3CA), and immunomarkers (eg, tumour-infiltrating lymphocytes and PD-L1). New biomarker combinations are
S0140-6736(20)32381-3
the basis for increasingly complex diagnostic algorithms. Neoadjuvant combination therapy, often including targeted
This online publication has been
corrected. The corrected version agents, is a standard of care (especially in HER2-positive and triple-negative breast cancer), and the basis for
first appeared at thelancet.com de-escalation of surgery in the breast and axilla and for risk-adapted post-neoadjuvant strategies. Radiotherapy
on May 6, 2021 remains an important cornerstone of breast cancer therapy, but de-escalation schemes have become the standard of
German Breast Group, care. ER-positive tumours are treated with 5–10 years of endocrine therapy and chemotherapy, based on an individual
Neu-Isenburg, Germany risk assessment. For metastatic breast cancer, standard therapy options include targeted approaches such as CDK4
(Prof S Loibl MD,
Prof C Denkert MD); Centre for
and CDK6 inhibitors, PI3K inhibitors, PARP inhibitors, and anti-PD-L1 immunotherapy, depending on tumour type
Haematology and Oncology and molecular profile. This range of treatment options reflects the complexity of breast cancer therapy today.
Bethanien, Frankfurt, Germany
(Prof S Loibl); Department of
Radiation Oncology, Iridium
Epidemiology and risk factors Next-generation sequencing in breast cancer is based
Kankernetwerk, Antwerp, Worldwide, breast cancer accounts for about 30% of on gene panels, which include, in addition to BRCA
Belgium (Prof P Poortmans MD); female cancers, and has a mortality-to-incidence ratio genes, PALB2, ATM, CHEK2, RAD51C, BARD1, and
University of Antwerp, Faculty of 15%.1 Worldwide incidence varies between 27 in TP53, among others. The partner and localiser of BRCA2
of Medicine and Health
100 000 (Africa and east Asia) and 97 in 100 000 (North (PALB2) is a protein that promotes the localisation and
Sciences, Antwerp, Belgium
(Prof P Poortmans); Breast America), reflecting the association between breast stability of BRCA2.7 Mono-allelic PALB2 germline muta
Service, Department of cancer incidence and the degree of economic develop tions lead to a 53% increased risk of breast, 2–3% increased
Surgery, Memorial Sloan ment and associated social and lifestyle factors.2 In risk of pancreatic, and 5% increased risk of ovarian
Kettering Cancer Center,
contrast, death rates continue to decline, but not cancer.8,9,10 Several genetic syndromes (eg, Lynch syn
New York, NY, USA
(Prof M Morrow MD); Institute everywhere. Declines in breast cancer mortality could drome) are associated with an increased risk of breast
of Pathology, Philipps be further accelerated by expanding access to high- cancer, although such syndromes have a low to moderate
University of Marburg, quality prevention, early detection, and treatment penetrance and are rare in the general population.11
Marburg, Germany
services to all women, not neglecting the vast differences National guidelines for genetic testing guide the
(Prof C Denkert); University
Hospital Marburg, Marburg, in access to these services.3,4 therapeutic procedure after personal and family history
Germany (Prof C Denkert); About 10% of all cases of breast cancer are related to taking, risk assessment, and genetic counselling.12
European Institute of Oncology genetic predisposition or family history, with variances by A high proportion of breast cancer cases might be
IRCCS, Milan, Italy
(Prof G Curigliano MD);
country and ethnicity. The most common germline attributed to pregnancy-associated factors, hormonal
University of Milano, Milan, mutations associated with breast cancer are in the BRCA1 therapy, lifestyle factors (ie, obesity, physical inactivity,
Italy (Prof G Curigliano) and BRCA2 genes, with an average cumulative lifetime alcohol intake, low-fibre diet, and smoking), and other
Correspondence to: risk of about 70%.5,6 risk factors (panel 1).13 In high-income countries, more
Prof Sibylle Loibl, German Breast than a third of cases of breast cancer seem to be
Group, Neu-Isenburg 63263,
preventable through lifestyle changes.13 There is a
Germany
[email protected] Search strategy and selection criteria long debate on whether oral hormonal contraceptives
Data for this Seminar were identified by searches of MEDLINE, increase the risk of breast cancer; the absolute risk is
PubMed, German Association of the Scientific Medical small and not associated with an increased risk of
Societies Guideline Register/Clinical Practice Guidelines, and mortality.14 Menopausal hormone therapy, on the other
references from relevant articles between Jan 1, 2016, and hand, has been more clearly shown to increase the risk of
Dec 31, 2020, using the search term “breast cancer” in breast cancer in women.15
combination with specific terms covering the different steps
of diagnosis and treatment as appropriate. We mostly Screening
selected literature published in the past 5 years, but did not Eight randomised clinical trials have shown that
exclude older publications that are commonly referenced and screening mammography reduces breast cancer mortality
highly regarded. We have arbitrarily chosen clinical studies by at least 20%.16 Conventional screening mammography
with the highest level of evidence or the highest number of detects 2–8 cancers per 1000 mammograms, which is
most recent meta-analysis and review articles. Abstracts and increased by 1·6 cancers per 1000 mammograms with the
reports from meetings that have not yet been published as use of digital breast tomosynthesis.17 Ultrasonography
full papers were also cited to provide readers with up-to-date screening, particularly in women with dense breasts,
literature. Only articles published in English and human detects an additional 4·4 cancers per 1000 screening
studies were included. examinations, but the positive predictive value of
ultrasonography is only 3–8%.18 MRI screening is
Panel 2: Open questions and their current status in breast cancer diagnosis and therapy controversies
Molecular classification How long should endocrine therapy be given?
How can we distinguish between luminal A and luminal B type Status: resolved. Based on risk, endocrine therapy for longer
tumours? than 5 years can be recommended for individual patients.
Status: resolved. Proliferation marker protein Ki-67, as well as What patients can be safely offered de-escalated HER2-positive
gene expression profiling, can be used to identify low-risk therapy?
tumours. Status: partly resolved. Patients at low risk of breast cancer
Limitation: all methods are clinically valid for prediction of relapse can be treated with less chemotherapy and trastuzumab
low-risk status, but the concordance between methods is low. instead of standard therapy.
What is the best treatment for tumours with low (1–10%) Can patients undergo sentinel node biopsy after neoadjuvant
ER expression? chemotherapy?
Status: not resolved. The biology of these tumours is similar to Status: partly resolved. In principle, yes, but the pre-
that of triple-negative breast cancer (TNBC), but patients are neoadjuvant chemotherapy status needs to be considered.
not eligible for TNBC trials and therapy options.
Can we use extreme hypofractionation (eg, radiotherapy in 1 week)
How do we address differences in ER, PR, and HER2 (ERBB2) in more patient subgroups?
expression between primary tumours and residual disease? Status: partly resolved. The FAST-Forward trial
Status: not resolved. In general, follow the initial diagnosis. (ISRCTN19906132) reported that 26 Gy in five fractions over
However, the level of evidence is low. 1 week results in non-inferior local recurrence rates and normal
How do we identify patients with TNBC that are eligible for tissue effects for breast and chest wall radiotherapy. Long-term
immunotherapy? follow-up evaluating late effects of locoregional radiotherapy is
Status: partly resolved. In the metastatic setting, PD-L1 is a ongoing.
biomarker of eligibility for checkpoint inhibitor therapy. In the Treatment of metastatic breast cancer
neoadjuvant setting, however, PD-L1 expression is not a valid What is the best treatment sequence in hormone receptor-positive,
biomarker to select for checkpoint inhibitor therapy. HER2-negative metastatic breast cancer?
Treatment of early breast cancer Status: unresolved. There are no clear data on the optimal
How to best identify patients with luminal, node-negative breast therapeutic sequence for these patients.
cancer for chemotherapy? Does chemotherapy have a role in patients with hormone receptor-
Status: partly resolved. Currently, a combination of positive, HER2-negative breast cancer?
clinicopathological markers and genomic assays is Status: partly resolved. Targeted agents seem to have pushed
recommended to identify patients at high risk of breast cancer chemotherapy to third-line treatment strategies, but
relapse. monochemotherapy can be less toxic than targeted agents plus
Which patients with TNBC benefit from carboplatin? endocrine therapy. Direct comparisons are scarce.
Status: partly resolved. Pathological complete response can be Do patients with primary metastatic breast cancer benefit from
increased with carboplatin-based therapy, but no conclusive surgery?
data on long-term outcomes are yet available. Status: partly resolved. Not yet conclusively answered, but there
Do all patients without pathological complete response need are no data suggesting the opposite (harm from surgery).
capecitabine as post-neoadjuvant therapy in TNBC? How do we address differences in ER, PR, and HER2 status between
Status: partly resolved. A preplanned subgroup analysis of a primary tumour and metastases?
phase 3 trial (NCT00130533) showed that capecitabine Status: partly resolved. Not yet conclusively answered.
increases disease-free survival and overall survival in non-basal The general recommendation is to follow the most recent
patients. This effect might be overestimated, considering the histological or immunophenotypic findings, although the level
data from a pooled analysis of 12 randomised trials. of evidence is low.
Diagnosis and therapy: current controversies without changing treatment recommendations,43 so that
and scientific discussions treating low-hormone receptor breast cancer as TNBC
There are still controversies around every aspect of would be the logical consequence. This is one of several
breast cancer diagnosis and care. For example, it has examples of controversy around treatment individu
been shown that tumours with low-hormone receptor alisation, especially for HER2-positive disease, but also
expression are biologically similar to TNBC. The American for TNBC (panel 2). Normally, de-escalation refers to
Society of Clinical Oncology and the College of American optimisation of treatment. Although breast cancer
Pathologists have recently defined low-ER tumours screening has been widely adopted in many high-income
as tumours with ER expression between 1% and 10%, countries, it is unclear to what extent this has led to an
overdiagnosis of non-invasive breast lesions (ie, ductal invasive disease-free survival (from 77%, with trastuzumab,
carcinoma in situ), which are associated with a high risk to 88%, with trastuzumab emtansine).47 These results are
of developing invasive breast cancer, but have a minimal very homogeneous and independent of the extent of
risk of breast cancer mortality. How effective screening residual disease and ER status.
is in terms of lowering breast cancer mortality is still Although primary surgery is highly effective, the
debated, considering that the increased rate of detection of widespread use of neoadjuvant therapy in early-stage breast
ductal carcinoma in situ has not been accompanied by a cancer allows further de-escalation of surgery in the breast
parallel decrease in invasive cancer incidence or breast and axilla, converting approximately 40% of patients with
cancer mortality. The increased rate of diagnosis of HER2-positive breast cancer and TNBC initially requiring
smaller invasive breast cancers has led to the discussion mastectomy to breast-conserving surgery candidates.48,49
of whether local therapy and systemic treatment need to The use of breast-conserving surgery post-neoadjuvant
be de-escalated to avoid harm. The increasing rates of therapy has been limited by the inability to reliably
pathological complete response with modern systemic distinguish between viable and non-viable tumour on post-
therapy have led to trials investigating the accuracy neoadjuvant therapy imaging, and by the inappropriate
of determining pathological complete response non-sur belief that pathological complete response and excision of
gically, in preparation for studies examining the safety of the entire initial tumour volume are both required
eliminating surgery altogether. In the absence of clear data for breast-conserving surgery in patients with larger
indicating the safety of de-escalation, the tendency is still tumours.50 The Early Breast Cancer Trialists’ Collaborative
to overtreat some patients to avoid their undertreatment. Group (EBCTCG) meta-analysis of ten randomised trials
(1983–2002) of neoadjuvant therapy versus adjuvant
Early breast cancer: neoadjuvant treatment therapy showed a 3·2% (95% CI 0·6–5·8%; p=0·01)
concept increase in locoregional recurrence in patients having
Neoadjuvant therapy (mainly chemotherapy with breast-conserving surgery post-neoadjuvant therapy,
targeted agents) has been widely accepted as a standard compared with those having the planned surgery first,
of care, especially in HER2-positive breast cancer and which raised some concerns. However, locoregional
TNBC, even when the disease is operable. The general recurrence was no more frequent in those requiring
concept is to use the same systemic therapy as would neoadjuvant therapy to downstage to breast-conserving
be given postoperatively before surgery, followed by surgery than in those who were candidates for breast-
surgery and irradiation and further post-neoadjuvant conserving surgery at presentation. Many of the studies in
systemic therapy, if required. Primary endocrine therapy the meta-analysis did not require negative resection
is used in ER-positive breast cancer when primary margins, and some of them required no surgery to the
surgery is contraindicated due to comorbidities, or in breast at all, suggesting that these findings probably reflect
patients with endocrine-responsive tumours desiring incomplete familiarity with post-neoadjuvant therapy
downstaging to breast conservation. The observation that imaging and surgery during that time, and highlighting
patients achieving a pathological complete response have the importance of multidisciplinary teamwork.51,52
significantly better disease-free survival and overall The use of neoadjuvant chemotherapy reduces nodal
survival than patients with residual disease44 has led to positivity among clinically node-negative (cN0) and
studies examining the use of additional systemic therapy cN-positive patients. In patients with cN0 status before
in patients without pathological complete response. In the start of neoadjuvant therapy, sentinel lymph node
the CREATE-X trial, adjuvant capecitabine improved identification rates (94–96%), false-negative rates (6–7%),
disease-free survival and overall survival after neoadju and nodal recurrence rates (<1·5%) mirror those seen in
vant anthracycline and taxanes-based chemotherapy in patients who undergo primary surgery.53–56 High rates of
patients with HER2-negative breast cancer.45 Extrapolation nodal pathological complete response in patients with
of these results to clinical practice is controversial cN-positive status receiving neoadjuvant therapy57,58 led to
because only patients with TNBC benefited from this four prospective multicentre trials evaluating sentinel
approach, and none of the patients in the trial received lymph node biopsy accuracy in this setting (table 1).55–59
carboplatin as part of the neoadjuvant regimen. In False-negative rates were largely determined by the
addition, patients with TNBC who do not reach patho number of sentinel lymph nodes retrieved. In a
logical complete response are generally considered to meta-analysis including 1921 patients with biopsy-proven
be chemoresistant, and capecitabine is unlikely to rescue nodal metastases, the sentinel lymph node identification
these patients.46 Nevertheless, most national and rate was 90% with a 14% false-negative rate, which fell
international guidelines recommend that capecitabine is to 4% with removal of three or more sentinel lymph
at least considered for these patients. The KATHERINE nodes.60 In a single-institution study, three or more
trial showed that switching from antibody-based anti- negative sentinel lymph nodes were retrieved and axillary
HER2 neoadjuvant therapy to trastuzumab emtansine lymph node dissection was avoided in 237 (42%) of
(an antibody–drug conjugate) after surgery in patients 573 patients who became cN0 after neoadjuvant therapy.61
without pathological complete response improved Another approach to decrease false negative rates of
dissection and smaller in case of regional radiotherapy is yet to be defined, although early evaluations are
without coverage of the chest wall. The EBCTCG encouraging.90–92
meta-analysis of the effect of radiotherapy after breast- Moderate hypofractionation (40–42·5 Gy in 15–16 ses
conserving surgery involving individual patient data of sions over 3 weeks) was shown to be non-inferior in terms
10 801 women from 17 randomised trials showed reduc of outcome and cosmetic result, compared with 50 Gy
tions in 10 year recurrences rates of 15·4% in patients with over 5 weeks, and consequently became the preferred
negative nodes and 21·2% in patients with positive nodes, scheme for most if not all patients.71,93 Subsequent research
and reductions in 15-year overall mortality rates of 3·3% demonstrated that a 1 week radiotherapy schedule to the
(patients with negative nodes) and 8·5% (patients with breast or the chest wall, delivering 26 Gy in five sessions
positive nodes).82 of 5·2 Gy, is non-inferior to the 3 week schedule for local
The indications for lymph node radiotherapy increased tumour control, and is as safe in terms of normal tissue
following these two EBCTCG meta-analyses81,82 and a effects up to 5 years.94 Ongoing, long-term follow-up and a
third meta-analysis83 of regional lymph node irradiation nodal substudy will show the influence of the ultrafast
involving 13 500 women in 14 trials. Furthermore, 1 week hypofractionation schedule on late cardiovascular
especially in patients at high risk, the decreasing toxicity.95
frequency of axillary surgery is compensated by an The sharp decrease in local recurrence rates has also
increasing use of nodal radiotherapy, while avoidance of led to the development of partial breast radiotherapy,
both surgery and radiotherapy is possible in patients which decreases the treatment burden by reducing both
with limited nodal involvement and no high-risk the treatment duration and the treated volumes. Several
features.80,84 techniques are available and can be grouped into
De-escalation of radiotherapy in patients at low risk, brachytherapy, intra-operative radiotherapy, and external
involving combinations of decreased number of sessions, beam radiotherapy.96–99 The two basic principles behind
size of target volumes, or both, and lower doses and partial breast radiotherapy include proper selection of
shorter treatment duration, includes anatomy-based target patients with low-risk breast cancer, and the ability to
volume contouring, hypofractionation, decreased use of a deliver an adequate tumouricidal dose to the target
tumour bed boost dose, and (accelerated) partial breast volume.100,101 If these two principles are respected,
irradiation.85–88 outcomes will not be inferior to whole breast radio
A major shift from the conventional field-based radio therapy, independently of the used technique.102
therapy setup towards an anatomically-defined, target All these developments lower the burden of radio
volume-based treatment planning and delivery greatly therapy for patients with breast cancer and improve the
facilitates proper delivery of the prescribed dose to the integration of (shorter courses of) radiotherapy into the
target volumes, while respecting the dose and volume overall multidisciplinary workflow (table 3).
defined constraints for normal tissues.70,79,89 The extent Current challenges include the integration and
to which this will decrease late normal-tissue toxicity optimisation of radiotherapy with breast reconstruction,
Table 3: Summary of a short selection of ongoing clinical trials involving radiation therapy
identifying patients in whom radiotherapy can be omitted younger than 35 years.121 Patients without an indication for
without jeopardising outcomes including quality of life, adjuvant chemotherapy, which implies a lower risk of
and selective treatment escalation in patients at high risk, recurrence, can be treated with tamoxifen alone. Quality
especially in case of resistance to neoadjuvant therapy.31,103–105 of life deteriorates when ovarian function suppression
The ultimate aim is to achieve individualised, risk-adapted is used, even more so when an aromatase inhibitor is
radiotherapy, combining a variety of biomarkers with novel added instead of tamoxifen, mainly because of an increase
applications of artificial intelligence.106–108 in vasomotor symptoms (which resolve after the end
of therapy).122 Patients who are prescribed adjuvant
Early breast cancer: systemic therapy tamoxifen after chemotherapy and remain premeno
Endocrine therapy pausal, or resume ovarian function after a temporary
Endocrine therapy for 5–10 years is the standard treatment chemotherapy-induced ovarian failure, benefit from the
for women with ER-positive early breast cancer. For addition of ovarian function suppression to tamoxifen, as
postmenopausal women, options include tamoxifen or a shown by the ASTRRA trial.123
steroidal (exemestane) or non-steroidal (letrozole or Starting ovarian function suppression 2 weeks before
anastrozole) aromatase inhibitor. Front-line therapy with the first chemotherapy dose should be advised for
an aromatase inhibitor results in a significant absolute preservation of ovarian function in women between
risk reduction of recurrence at 10 years of 3·6% and in 35 and 40 years and is independent of the ER status of the
an increase in overall survival of 2·1% compared with tumour.124 Pregnancy after breast cancer is not contra
tamoxifen. The sequential approach of aromatase inhi indicated, since there are no data showing an adverse
bitor after 2–5 years of tamoxifen results in a smaller outcome.125 Tamoxifen needs to be stopped at least
benefit than the aromatase inhibitor upfront therapy, but 2–3 months before conception. It is recommended to
it still results in significant risk reduction for breast resume endocrine therapy after delivery and lactation, and
cancer recurrence of 2·0% and death of 1·5% compared to complete at least 5 years of therapy. The optimal timing
with tamoxifen alone.109,110 Aromatase inhibitor therapy of pregnancy after a breast cancer diagnosis and treatment
has been shown to provide greater benefit in patients is an area of uncertainty, and is based on the individual risk
with advanced stage (II–III), high-grade, HER2-positive, and age of the patient. The PREFER study (NCT02895165)
or highly proliferative disease. Despite little supporting and the prospective POSITIVE study (NCT02308085) are
data, aromatase inhibitors are also the preferred option collecting important data on fertility preser vation and
for lobular cancers based on the results of the BIG selection of ovarian function preser vation strategies;
1-98 trial.111 The standard duration of endocrine therapy POSITIVE will also assess the feasibility and safety of
with aromatase inhibitors is 5 years, especially for stage I endocrine therapy discontinuation to attempt pregnancy
disease.112 The role of adjuvant therapy extended for up to after breast cancer diagnosis and treatment.
10 years has been investigated in several trials and CDK4 and CDK6 inhibitors (palbociclib, abemaciclib,
data suggest that continuation of endocrine therapy and ribociclib) in addition to endocrine therapy in
reduces the risk of recurrence in patients at high risk patients at high or very high risk are currently being
(node-positive, high genomic score).113–117 Patients with evaluated in several phase 3 trials (PENELOPE-B
ER-positive disease remain at risk of recurrence even [NCT01864746], 1 year; PALLAS [NCT02513394] and
after 10 years, and the decision to extend adjuvant therapy monarchE [NCT03155997], 2 years; NATALEE
needs to take into account and balance potential benefits [NCT03701334], 3 years). All three CDK4 and CDK6
against toxicity and impaired quality of life.118 inhibitors have been shown to improve progression-free
Patients in the premenopause with hormone receptor- survival and overall survival in endocrine-sensitive and
positive, HER2-negative, lymph node-positive breast endocrine-resistant metastatic breast cancer.126 The
cancer benefit from combined endocrine therapy and PENELOPE-B trial did not show that the addition of
chemotherapy. Recent data from the phase 3 RxPONDER 1 year of palbociclib to standard adjuvant endocrine
trial (NCT01272037) showed that the addition of chemo therapy improves 3 year invasive-disease free survival in
therapy to endocrine therapy improved 5 year invasive patients at high risk of relapse after neoadjuvant
disease-free survival and overall survival in premenopausal chemotherapy (81·2% with palbociclib vs 77·7% with
women that were also of low biological risk by multigene placebo).127 In the PALLAS study, palbociclib given for
testing.119 2 years did not improve the outcome (3 years invasive
In premenopausal women with ER-positive early breast disease-free survival) of early breast cancer in patients
cancer, based on the SOFT and TEXT trials, ovarian at intermediate and high risk of recurrence (88·2% for
function suppression in combination with an aromatase palbociclib plus endocrine therapy vs 88·5% for
inhibitor or tamoxifen reduces the recurrence rate endocrine therapy alone; hazard ratio [HR] 0·93 [95% CI
when compared with tamoxifen alone, and is therefore 0·76–1·15]; p=0·51).128 The monarchE study, in which
recommended in all women with an indication for abemaciclib was used in an exclusively high-risk breast
chemotherapy.113,120 Ovarian function suppression plus cancer population, did show a 3·5% absolute difference
an aromatase inhibitor is recommended for patients in 2 year invasive disease-free survival rates after a
median follow-up of 15 months: 92·2% for abemaciclib One adjuvant therapy study, mainly in patients with pT1
versus 88·7% for endocrine therapy alone (HR 0·75 and node-negative status, showed improved disease-free
[95% CI 0·60–0·93]; p=0·01), which is rather short for a survival with a carboplatin anthracycline-free combina
HER2-negative, hormone receptor-positive breast cancer tion over epirubicin, fluorouracil, and cyclophosphamide
population.129 followed by docetaxel.149 The carboplatin effect in early
breast cancer seems to be independent of BRCA status.150
Chemotherapy in patients with ER-positive breast To date, PARP inhibitors have not been shown to
cancer and TNBC improve short-term or long-term outcomes in breast
The use of chemotherapy generally reduces the risk cancer. The only phase 3 trial of PARP inhibitors for
of recurrence by about 30% in selected patients. The breast cancer to date did not show an increased
absolute benefit from neoadjuvant or adjuvant chemo pathological complete response rate with the addition
therapy depends on the risk of recurrence.130 When of veliparib (probably the PARP inhibitor with the least
neoadjuvant or adjuvant chemotherapy is indicated, the activity) to paclitaxel plus carboplatin followed by
optimal regimen consists of a taxane-based regimen with doxorubicin–cyclophosphamide.147 Smaller studies using
or without anthra cyclines in sequence. The use of either olaparib or talazoparib have shown some
anthracyclines is often controversially debated, but it promising effects. The full results of the OlympiA
seems to be necessary in patients at high risk.131,132 (NCT02032823) study, where olaparib 600 mg was given
Fluorouracil as part of adjuvant chemotherapy does for 1 year after standard neoadjuvant or adjuvant chemo
not seem to add benefit to an anthracycline and therapy in patients with germline BRCA-mutated,
taxane-based therapy.133 Dose-dense or dose-intensified HER2-negative breast cancer, with positive preliminary
chemotherapy is generally superior to conventionally findings in invasive disease-free survival in the olaparib
dosed therapy. The relative risk reduction is independent group, are awaited (figure 1B).
of prognostic factors and the absolute benefit varies Addition of the anti-PD-1 antibody pembrolizumab
with the level of risk.134 The most important clinical and to neoadjuvant paclitaxel and carboplatin followed by
pathological determinants to stratify risk and to identify doxorubicin–cyclophosphamide increased the patho
candidates for additional chemotherapy are: advanced- logical complete response rate by up to 64%. The effect
stage disease with nodal involvement, tumour size, less was independent of PD-L1 status and mainly seen in
endocrine-responsive disease (low expression of ER, node-positive breast cancer.151 Very similar results could
PR, or both), high grade or high proliferative index, be observed with atezolizumab being added to nab-
patient age, and lymphovascular invasion.135 To better paclitaxel followed by doxorubicin–cyclophosphamide
stratify the risk and identify patients who might derive every 2 weeks.152 This combination might change
benefit from chemo therapy, multigene assays can the primary therapy in high-risk early TNBC. In all
be used when available, especially in node-negative neoadjuvant phase 3 breast cancer trials investigating a
ER-positive, HER2-negative breast cancer to support checkpoint inhibitor, including the currently recruiting
decision making (figure 1A).136–141 In postmenopausal GeparDouze trial (NCT03281954), patients continued
patients with up to three positive nodes and low or taking the checkpoint inhibitor after surgery for up to
intermediate genomic score, there is no indication to 1 year. The rational for this decision is not clear, but it is
add chemotherapy, although chemotherapy is recom in analogy to the anti-HER2 therapy in HER2-positive
mended for patients with a high genomic score. early breast cancer.
Regarding the use of chemotherapy in premenopausal
women with no nodal involvement, a retrospective Management of HER2-positive early breast cancer
analysis questioned a potential benefit for patients The addition of anti-HER2 therapy (mainly trastuzumab
with tumours harbouring an intermediate recurrence and pertuzumab) to chemotherapy has changed the
score.142 Since no prospective data for lobular cancers natural history of this disease.153 The vast majority of
are available, the same recommendations apply to these patients with a tumour of 2 cm or larger or nodal
patients, although acknowledging that their chemo involvement receive neoadjuvant trastuzumab plus
sensitivity is much lower.143 pertuzumab, in addition to doxorubicin–cyclophos
In women with early TNBC, an anthracycline and phamide or epirubicin–cyclophosphamide followed by a
taxane-based chemotherapy is the mainstay of treatment. taxane, or in addition to docetaxel–carboplatin, which is
Whether an anthracycline-free regimen is appropriate associated with higher toxicity. This regimen increased
for these patients is controversial. Several clinical trials the pathological complete response rate to about 65–70%
incorporating platinum salts into standard regimens and led to an improvement in event-free survival and
have shown an associated absolute improvement in disease-free survival.154,155 Attempts have been made to
pathological complete response rates of about 15%.144–147 decrease either the duration of anti-HER2 therapy or
The effect on long-term disease-free survival and overall to reduce the use of chemotherapy agents. None
survival is less convincing, due to the small size of some of the randomised trials using a shorter duration of
trials and the absence of long-term follow-up in others.148 trastuzumab convincingly showed that such a reduction
A
HR-positive, HER2-negative early breast cancer
Surgery
Adjuvant treatment
High ER and PR expression; pT1a–pT1b, pN0; Intermediate to high ER and PR expression; pT1c, pT2, pN0 or Low to intermediate ER and PR expression; T3, N2–N3, or both;
low proliferation, low grade, or low genomic risk pN1 (1–3); intermediate or high proliferation or grade; extensive high proliferation or grade, intermediate genomic risk, or both
LVI, intermediate genomic risk, or both
Tamoxifen; if contraindicated, AI (plus GnRH analogue if Tamoxifen or AI (plus GnRH analogue if premenopausal); Chemotherapy with anthracycline followed by taxanes; AI (plus
premenopausal) chemotherapy with anthracycline followed by taxanes (consider GnRH or LHRH analogue if premenopausal)
case by case)
B
HER2-
Trastuzumab plus pertuzumab plus positive TNBC
chemotherapy (including taxanes, HER2-positive, triple-negative Follow-up
with or without anthracyclines or early breast cancer
carboplatinum)†
Neoadjuvant therapy* Yes Trastuzumab with or without pertuzumab for
HER2- 12 months
Chemotherapy (including positive
Surgery according to residual Post-neoadjuvant pCR
anthracycline and taxanes, with
disease setting
or without carboplatinum)‡
TNBC
TNBC
No Consider capecitabine for 6–8 courses
TNBC
HER2-positive
HR-negative HR-positive
Follow-up or Chemotherapy with Chemotherapy with Trastuzumab plus Tamoxifen, Chemotherapy with Chemotherapy with Trastuzumab plus
chemotherapy with paclitaxel plus anthracycline pertuzumab in if contraindicated, AI paclitaxel plus anthracycline pertuzumab, if N+
paclitaxel plus trastuzumab for followed by taxanes addition to (plus GnRH analogue trastuzumab for followed by taxanes or at high risk
trastuzumab for 1 year; consider with concurrent chemotherapy, if if premenoapausal) 1 year plus AI or with concurrent
1 year addition of trastuzumab with or N+ or high-risk or chemotherapy tamoxifen with or trastuzumab with or
anthracyclines in without with paclitaxel plus without GnRH without
selected patients pertuzumab§ trastuzumab for analogue if pertuzumab§
continued for 1 year, followed by premenopausal continued for
12 months endocrine therapy patient; consider 12 months and AI
addition of (plus GnRH
anthracyclines in analogue if
selected patients premenopausal)
A
Diagnosis of ER-positive, HER2-negative ABC
Sequential single-agent
chemotherapy (preferred)
or taxanes*
Maintenance ET after
chemotherapy to maintain benefit
Second line and beyond
B
Diagnosis of HER2-positive ABC
Previously untreated with anti-HER2 Previously treated with Patients who can't have Previously treated with
therapy (neo)adjuvant anti-HER2 therapy chemotherapy or with a long DFI, (neo)adjuvant pertuzumab plus
minimal disease burden, ER-positive trastuzumab with a DFI
disease, or all <6–12 months
No progression
Third line
capecitabine agent ER-positive
(preferred for patients
with active or known
CNS metastases)
and beyond
Fourth line
Other option not previously used but
continue to block the HER2 pathway
plus lapatinib is another treatment option (plus endocrine response rate of 61% in a phase 1/2 study.194 The main side-
therapy in HER-2 positive, hormone receptor-positive effect, in addition to nausea (78% of patients; any grade),
tumours). Neratinib, a pan-ERBB tyrosine kinase inhibitor, decreased neutrophil count (35% of patients), and anaemia
in combination with paclitaxel was not superior to (30% of patients; any grade) was interstitial lung disease
paclitaxel plus trastuzumab as a first-line therapy, but (14% of patients).194 Whether the drug is more effective
seemed to delay the onset of brain metastases.191 Neratinib than trastuzumab emtansine is being investigated in an
plus capecitabine in further line was superior to lapatinib ongoing trial (NCT03529110). Trastuzumab deruxtecan
plus capecitabine.192 Compared with a placebo, the highly has also shown an overall response rate of 37% in heavily
selective anti-HER2 tyrosine kinase inhibitor tucatinib in pretreated patients with HER2-low disease.195 These new
addition to capecitabine and trastuzumab has resulted in anti-HER2 drugs will expand the armamentarium for
significantly higher progression-free survival and overall treating HER2-positive breast cancer, for which continuous
survival in the overall population and in patients with anti-HER2 treatment is key (figure 3B).
brain metastases after pretreatment with trastuzumab,
pertuzumab, and trastuzumab emtansine, as shown by Management of metastatic TNBC
the HER2CLIMB study.193 Trastuzumab deruxtecan, an Atezolizumab, an immune checkpoint inhibitor, plus nab-
antibody–drug conjugate, has shown a high overall paclitaxel improved progression-free survival by about
C
Diagnosis of triple-negative ABC
PD-L1-positive† PD-L1 negative (or anti-PD-L1 unavailable) BRCA wild type (or BRCA status unknown) BRCA mutation†
Nab-paclitaxel plus atezolizumab or Combination chemotherapy (patients Sequential single-agent chemotherapy PARPi
paclitaxel plus pembrolizumab with rapid progression, visceral crisis,
and need for rapid symptoms and disease
control)
Previously untreated with anthracycline or taxanes Previously treated with anthracycline or taxanes
Figure 3: Treatment algorithm for ER-positive and HER2-negative metastatic breast cancer (A), HER2-positive metastatic breast cancer (B), and triple-negative metastatic breast cancer (C)
ABC=advanced breast cancer. AI=aromatase inhibitor. DFI=disease-free interval. ET=endocrine therapy. PARPi=poly(ADP-ribose) polymerase inhibitor. *Rechallenge with taxanes or anthracycline is
possible (if cumulative dose not reached and DFI ≥12 months). †Patients with PD-L1-positive or BRCA-mutated breast cancer should first receive a checkpoint inhibitor with taxane, then PARPi
(no data available for checkpoint inhibitors as second-line threapy).
2·5 months in TNBC expressing more than 1% PD-L1.196 germline BRCA1-mutant or BRCA2-mutant metastatic
The overall survival analysis indicated no significant TNBC was also superior to chemotherapy alone.201 The
difference between the treatment groups, but suggests a therapeutic implications of somatic BRCA1 or BRCA2
clinically meaningful overall survival benefit (of about mutations in breast cancer need to be further explored
10 months) with atezolizumab plus nab-paclitaxel in the within a research setting, and should not be considered
PD-L1-positive population.197 The KEYNOTE-355 study, an indication for PARP inhibitors in clinical practice.
investigating the efficacy of pembrolizumab in combi The optimal sequence in patients with PD-L1-positive
nation with one of three chemo therapy options (nab- and germline BRCA1 or BRCA2 mutations would first
paclitaxel, paclitaxel, or carboplatin–gemcitabine) reported be checkpoint inhibitor-based therapy and then the
the pembrolizumab combination to have a positive effect PARP inhibitor. In a study setting, only 7% of patients
on progression-free survival in PD-L1-positive metastatic with PD-L1-positive metastatic TNBC harboured a
TNBC (figure 3C).198 Conversely, atezolizumab in addition mutation; conversely, 50% of patients with the germline
to paclitaxel did not show a significant progression-free BRCA mutant had PD-L1-positive tumours, suggesting
survival benefit compared with paclitaxel alone.199 Taking that the PD-L1 positivity rate is independent from
all the relevant data into consideration, there is still germline BRCA status.202
controversy about the effect size of checkpoint inhibitors In all other patients with metastatic disease, chemo
in breast cancer, but checkpoint inhibitor monotherapy therapy remains the standard of care.
does not seem to be effective in breast cancer.200
Similarly to patients with ER-positive, HER2-negative Non-systemic options for metastatic breast cancer,
metastatic breast cancer, single-agent PARP inhibitor including local therapies
(talazoparib or olaparib) is a treatment option for The relation between tumour burden and outcome is
patients harbouring a germline BRCA1 or BRCA2 known for all stages of breast cancer. Therefore, radical
mutation.189,190 The combination of veliparib with treatments directed to at least part of the residual tumour
paclitaxel plus carboplatin as a first-line therapy for after systemic therapy are assumed to improve outcomes.203
Another possible mechanism is a so-called abscopal effect Several agents (ie, PARP inhibitors, checkpoint inhi
beyond the irradiated volume, influencing the distribution bitors, and PI3K inhibitors) approved in recent years
and growth of distant tumour deposits.204 work only in patients or tumours with a certain biomarker
Although several retrospective analyses205–207 suggested or mutation. The European Society for Medical Oncology
that local or locoregional surgery, radiotherapy, or both, has set a scale for actionability of molecular targets.216
improve overall survival, two prospective randomised New drugs, such as AKT inhibitors (eg, ipatasertib, tested
trials did not show a consistent and clear benefit with in the LOTUS trial,217 or capivasertib, tested in the PAKT
surgery, which might at least in part be attributed to trial218) show promising results, but the IPATunity130
methodological and regional issues.208,209 However, a trial failed to confirm the phase 2 data for ipatasertib
multicentre retrospective cohort including 4507 patients added to paclitaxel in first-line metastatic TNBC.219 There
with primary metastatic breast cancer showed that are also antibody–drug conjugates for the treatment of
radiotherapy with or without surgery, but not surgery TNBC and ER-positive, HER2-negative breast cancer,
alone, improved overall survival after adjustment for independently of any biomarker. Sacituzumab govitecan,
known prognostic factors and propensity score analysis.210 which targets TROP2 (TACSTD2) has been shown to
The ECOG-ACRIN 2108 trial (NCT01242800), which significantly improve progression-free survival and
randomly assigned 390 patients who did not progress overall survival in TNBC and shows promising phase 2
after 4–8 months of systemic therapy to continued results in hormone receptor-positive, HER2-negative
systemic therapy or early local therapy (consisting of metastatic breast cancer.220–222 The results of the histone
surgery to negative margins and standard of care deacetylase inhibitor entinostat E2112 trial (NCT02115282)
radiotherapy), showed no improvement in progression- are awaited.223 New endocrine agents (selective ER
free survival or overall survival for local therapy at a downregulators) are being developed to over come or
median follow-up of 53 months. Survival worsened by prevent endocrine resistance, which is based, for
3·3 times and local progression increased by 2·5 times instance, on ESR1 mutations.224
with local therapy in TNBC, leading the authors to A general focus is de-escalation, which, as discussed, is
conclude that local therapy should be reserved for patients controversial. Care is required not to jeopardise the
with stable metastases and symptomatic progression at progress made in the last 40 years. De-escalation in
the primary site.211 surgery has been a goal for many years, whereas in
Any palliative treatment should aim to deliver a good systemic and radiation therapy, de-escalation has only
compromise between symptom relief and treatment- become of interest more recently. There must be a careful
related burden, taking into account all other factors related balance between acceptable increase in the relapse risk
to the tumour, treatment, and patient. An emerging field and potential decrease of side-effects, including financial
concerns oligometastatic disease, most often defined as toxicity. Discussions are ongoing, but it remains vital that
up to five metastases.212 Although early data show all de-escalation measures are tested within clinical trials.
improved outcomes after radical metastases-directed “ASCO [American Society of Clinical Oncology] believes
therapy, these data are based upon a widely variable range that cancer clinical trials are vital to inform medical
of clinical scenarios, with different prognoses and decisions and improve cancer care and that all patients
requiring different therapeutic approaches.213 Most should have the opportunity to participate.”225 We are
patients can be treated with short courses of radiotherapy, convinced of this.
ranging between one and five of conventional or Contributors
stereotactic techniques, with palliative, radical, and even All authors contributed actively to the manuscript and approved the final
curative intentions. A special case is brain metastases, version.
which are seen in up to a third of metastatic breast cancer Declaration of interests
patients, most commonly at 1–3 years after metastatic SL reports grants and honorarium for lectures and advice boards paid to
institution from AbbVie, Amgen, AstraZeneca, Celgene, Novartis,
breast cancer diagnosis.214 Pfizer, Roche, and Daiichi-Sankyo; honorarium for lectures and advice
The progresses in diagnostic procedures and systemic boards paid to institution from Seattle Genetics, priME/Medscape, Lilly,
treatments improve the identification of metastatic Samsung, Eirgenix, BMS, Puma, and MSD; personal fees from Chugai;
breast cancer patients with a low overall disease burden, grants from Teva, Vifor, and Immunomedics outside the submitted
work; and has a patent (EP14153692.0) pending. PP reports a medical
who might benefit more from optimised locoregional advisor role for Sordina IORT Technologies outside the submitted work.
therapy and from metastases-directed treatments.215 MM reports personal fees from Genomic Health outside the submitted
All of this should be discussed in a multidisciplinary work. CD reports personal fees from Novartis, Roche, MSD Oncology,
tumour board, ideally one dedicated to metastatic and Daiichi Sankyo; grants from Myriad Genetics; is a cofounder and
shareholder of Sividon Diagnostics/Myriad (unrelated to the submitted
disease. work); has two patents pending (EP18209672 and EP20150702464), and a
patent Software pending (VMscope digital pathology). GC reports grants
Conclusion and future perspectives from Roche and Pfizer; and personal fees from Daichii Sankyo, MSD,
Future research in breast cancer will focus not only on and AstraZeneca outside the submitted work.
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