1360
www.thelancet.com/oncology Vol 18 October 2017
Articles
Ipatasertib plus paclitaxel versus placebo plus paclitaxel as
first-line therapy for metastatic triple-negative breast cancer
(LOTUS): a multicentre, randomised, double-blind,
placebo-controlled, phase 2 trial
Sung-Bae Kim*, Rebecca Dent*, Seock-Ah Im, Marc Espié, Sibel Blau, Antoinette R Tan, Steven J Isakoff, Mafalda Oliveira, Cristina Saura,
Matthew J Wongchenko, Amy V Kapp, Wai Y Chan, Stina M Singel, Daniel J Maslyar, José Baselga, on behalf of the LOTUS investigators†
Summary
Background The oral AKT inhibitor ipatasertib is being investigated in cancers with a high prevalence of PI3K/AKT
pathway activation, including triple-negative breast cancer. The LOTUS trial investigated the addition of ipatasertib to
paclitaxel as first-line therapy for triple-negative breast cancer.
Methods In this randomised, placebo-controlled, double-blind, phase 2 trial, women aged 18 years or older with
measurable, inoperable, locally advanced or metastatic triple-negative breast cancer previously untreated with
systemic therapy were recruited from 44 hospitals in South Korea, the USA, France, Spain, Taiwan, Singapore, Italy,
and Belgium. Enrolled patients were randomly assigned (1:1) to receive intravenous paclitaxel 80 mg/m² (days 1, 8,
15) with either ipatasertib 400 mg or placebo once per day (days 1–21) every 28 days until disease progression or
unacceptable toxicity. Randomisation was by stratified permuted blocks (block size of four) using an interactive
web-response system with three stratification criteria: previous (neo)adjuvant therapy, chemotherapy-free interval,
and tumour PTEN status. The co-primary endpoints were progression-free survival in the intention-to-treat population
and progression-free survival in the PTEN-low (by immunohistochemistry) population. This ongoing trial is registered
with ClinicalTrials.gov (NCT02162719).
Findings Between Sept 2, 2014, and Feb 4, 2016, 166 patients were assessed for eligibility and 124 patients were
enrolled and randomly assigned to paclitaxel plus ipatasertib (n=62) or paclitaxel plus placebo (n=62). Median
follow-up was 10·4 months (IQR 6·5–14·1) in the ipatasertib group and 10·2 months (6·0–13·6) in the placebo
group. Median progression-free survival in the intention-to-treat population was 6·2 months (95% CI 3·8–9·0) with
ipatasertib versus 4·9 months (3·6–5·4) with placebo (stratified hazard ratio [HR] 0·60, 95% CI 0·37–0·98; p=0·037)
and in the 48 patients with PTEN-low tumours, median progression-free survival was 6·2 months (95% CI 3·6–9·1)
with ipatasertib versus 3·7 months (1·9–7·3) with placebo (stratified HR 0·59, 95% CI 0·26–1·32, p=0·18). The most
common grade 3 or worse adverse events were diarrhoea (14 [23%] of 61 ipatasertib-treated patients vs none of
62 placebo-treated patients), neutrophil count decreased (five [8%] vs four [6%]), and neutropenia (six [10%] vs
one [2%]). No colitis, grade 4 diarrhoea, or treatment-related deaths were reported with ipatasertib. One treatment-
related death occurred in the placebo group. Serious adverse events were reported in 17 (28%) of 61 patients in the
ipatasertib group and nine (15%) of 62 patients in the placebo group.
Interpretation Progression-free survival was longer in patients who received ipatasertib than in those who received
placebo. To our knowledge, these are the first results supporting AKT-targeted therapy for triple-negative breast
cancer. Ipatasertib warrants further investigation for the treatment of triple-negative breast cancer.
Funding F Homann-La Roche.
Introduction
The PI3K/AKT signalling pathway plays a crucial part in
carcinogenesis, promoting cell survival and growth.
1,2
AKT is the central node of the PI3K/AKT pathway.
3
Phosphatidylinositol (3,4,5)-triphosphate, a direct
product of PI3K activity, promotes AKT tracking to the
cell membrane and association with other cell- signalling
proteins.
4
Full activation of AKT occurs via
phosphorylation at two threonine and serine residues,
leading to phosphorylation and regulation of numerous
cellular proteins, including mTORC1 and S6 kinase.
The PI3K/AKT signalling pathway is often activated in
breast cancer, and has attracted interest as a target in triple-
negative breast cancer.
5,6
Large-scale comp rehensive
genomic analyses have characterised the heterogeneous
nature of triple-negative breast cancer, including a
subgroup with genetic activation of the PI3K/AKT pathway
through activating mutations in PIK3CA or AKT1, and
alterations in PTEN.
7–9
Additionally, approximately half of
triple-negative breast cancers have deficient expression of
the tumour suppressor PTEN, which is associated with a
higher degree of AKT pathway activation.
2,10
Lancet Oncol 2017; 18: 1360–72
Published Online
August 8, 2017
http://dx.doi.org/10.1016/
S1470-2045(17)30450-3
See Comment page 1293
*Contributed equally
†Listed in the appendix
Department of Oncology, Asan
Medical Center, University of
Ulsan College of Medicine, Seoul,
South Korea (Prof S-B Kim MD);
Division of Medical Oncology,
National Cancer Centre,
Singapore, Singapore
(R Dent MD); Department of
Internal Medicine, Seoul
National University Hospital,
Cancer Research Institute, Seoul
National University College of
Medicine, Seoul, South Korea
(S-A Im MD); Breast Disease
Center, Hospital Saint Louis,
Paris, France (M Espié MD);
Northwest Medical Specialties
and Division of Oncology,
University of Washington,
Washington, WA, USA
(S Blau MD); Levine Cancer
Institute, Carolinas HealthCare
System, Charlotte, NC, USA
(A R Tan MD); Massachusetts
General Hospital, Boston, MA,
USA (S J Isakoff MD); Medical
Oncology Department, Vall
d’Hebron University Hospital,
Vall d’Hebron Institute of
Oncology, Barcelona, Spain
(M Oliveira MD, C Saura MD);
Genentech Inc, South
San Francisco, CA, USA
(M J Wongchenko BS,
A V Kapp PhD, W Y Chan PhD,
S M Singel MD, D J Maslyar MD);
and Memorial Sloan Kettering
Cancer Center, New York, NY,
USA (J Baselga MD)
Correspondence to:
Prof Sung-Bae Kim, Department
of Oncology, Asan Medical
Center, University of Ulsan
College of Medicine, Songpa-gu,
Seoul 05505, South Korea
sbkim3@amc.seoul.kr
Articles
www.thelancet.com/oncology Vol 18 October 2017
1361
See Online for appendix
Ipatasertib is a highly selective oral ATP-competitive
small-molecule AKT inhibitor.
11
In cell line and
xenograft models, ipatasertib showed activity in a
broad range of cancer types, including prostate, breast,
ovarian, colorectal, and non-small-cell lung cancers.
11
Sensitivity to ipatasertib tended to be associated with
high phosphorylated AKT levels, PTEN protein loss or
genetic mutations in PTEN, and PIK3CA mutations,
whereas KRAS and BRAF mutations were typically
associated with resistance to ipatasertib.
11
As PI3K/
AKT pathway activation is relevant for survival during
periods of mitotic stress,
12
the combination of
ipatasertib and taxanes was explored. Preclinical
studies showed synergy between ipatasertib and
taxanes.
13
Analysis of on-study tumour biopsy samples
from a phase 1 clinical study showed robust AKT
pathway inhibition by ipatasertib at clinically achievable
doses.
14
Based on these findings and its mechanism of action,
ipatasertib is under clinical assessment in cancers with a
high prevalence of PI3K/AKT pathway activation.
A phase 1 study
15
of single-agent ipatasertib in
52 pretreated patients with various tumour types,
including breast cancer, showed an acceptable safety
profile (characterised by gastrointestinal eects, asthenia
or fatigue, and rash) and preliminary antitumour activity.
Of note, many patients with disease stabilisation had
PI3K/AKT pathway-activating alterations in their
tumours. In breast cancer, the combination of ipatasertib
(400 mg once daily, days 1–21) with paclitaxel 90 mg/m²
per week (days 1, 8, and 15), repeated every 28 days, was
well tolerated and showed radiographic responses in the
phase 1b PAM4983g study.
13
We report results of a randomised phase 2 trial
investigating the addition of ipatasertib to paclitaxel as
first-line therapy for metastatic triple-negative breast
cancer.
Methods
Study design and participants
LOTUS is a randomised, double-blind, placebo-controlled,
phase 2 trial. Patients were enrolled at 44 hospitals in
South Korea, the USA, France, Spain, Taiwan, Singapore,
Italy, and Belgium (appendix pp 2–3).
Eligible patients were women aged 18 years or older,
with Eastern Cooperative Oncology Group performance
status 0 or 1, and locally advanced or metastatic triple-
negative breast cancer (defined as <1% tumour cell
expression of oestrogen and progesterone receptors and
negative HER2 status [fluorescence or chromogenic in-
situ hybridisation {FISH/CISH} HER2/CEP17 ratio <2·0,
or locally assessed immunohistochemistry 0 or 1 + {or 2+
but negative by FISH/CISH}]) not amenable to curative
resection. Patients had to have measurable disease
according to Response Evaluation Criteria in Solid
Tumors (RECIST; version 1.1) and adequate haema to-
logical, renal, hepatic, and cardiac functions. A formalin-
fixed paran-embedded tumour specimen was required
from all patients for central analysis of PTEN expression
before randomisation. The most recently obtained
tumour sample was requested for submission, but a
fresh biopsy sample was not required and primary
tumour samples were acceptable.
Previous systemic therapy for locally advanced or
metastatic disease was not permitted; however, previous
(neo)adjuvant chemotherapy, radiotherapy, or chemo radio-
therapy completed at least 6 months before the first dose
was allowed. Patients were ineligible if they had known
brain or spinal cord metastasis, ongoing grade 2 or worse
peripheral neuropathy or grade 2 or worse uncontrolled
or untreated hypercholesterolaemia or hyper tri-
glyceridaemia, or active small or large intestine
inflammation (such as Crohn’s disease or ulcerative colitis).
All patients provided written informed consent before
undergoing any study-specific procedures. Independent
Research in context
Evidence before this study
We searched PubMed to identify publications published
between Jan 1, 2001, and March 31, 2017, that included the
search terms “AKT”, “PI3K”, and “triple-negative breast
cancer”. We also searched PubMed for publications in the
same period describing assessment of ipatasertib using the
terms “ipatasertib” or “GDC-0068”. We did not use any
language restrictions in our search. No previous
randomised trials have investigated the targeting of AKT or
PI3K specifically in triple-negative breast cancer. Analyses of
single-arm studies in mesenchymal and metaplastic
triple-negative breast cancer have suggested a more
pronounced response to a combination of an mTOR
inhibitor, bevacizumab, and pegylated liposomal
doxorubicin in patients with PI3K/AKT/mTOR pathway
aberrations. A phase 1 study showed potent inhibition of
AKT signalling with ipatasertib, with notable activity in
metastatic breast cancer showing PTEN loss or PIK3CA/AKT
mutations.
Added value of this study
To our knowledge, these are the first prospective trial results
supporting AKT targeting in triple-negative breast cancer.
Prespecified analyses in the population of patients with
PIK3CA/AKT1/PTEN-altered tumours suggest efficacy of
ipatasertib in this population.
Implications of all of the available evidence
Our results support future investigation of ipatasertib plus
paclitaxel in diseases with high prevalence of PI3K/AKT
pathway activation, particularly in patients with
PIK3CA/AKT1/PTEN-altered tumours.
Articles
1362
www.thelancet.com/oncology Vol 18 October 2017
institutional review boards at all participating centres
approved the protocol and all study-related documents.
The protocol is available in the appendix.
Randomisation and masking
Eligible patients were randomly assigned (1:1) to either
ipatasertib plus paclitaxel or placebo plus paclitaxel by
investigators using an interactive web-response system
with an allocation sequence generated by Bracket Global
LCC (Reading, UK). Randomisation was by stratified
permuted blocks (block size of four). Randomisation was
stratified by three criteria: previous (neo)adjuvant
chemotherapy (yes vs no), chemotherapy-free interval
(≤12 vs >12 months vs no previous chemotherapy), and
central tumour PTEN status as assessed by
immunohistochemistry (H score 0 vs 1–150 vs >150). In
some cases, patients were randomly assigned before
PTEN status was available; for stratification, these
patients were assigned to the stratum with an H score
more than 150. This approach was adopted because if
patients were otherwise eligible and able to enrol on the
study, we did not consider it ethically acceptable to delay
their first-line treatment while waiting for centrally
assessed PTEN status or if tissue samples were inadequate
for central PTEN analysis. However, for stratified ecacy
analyses, the actual PTEN status (if known) was used.
The stratification factors of previous (neo)adjuvant
chemotherapy and chemotherapy-free interval partly
overlap. However, our intention was to try to balance the
treatment groups in this heterogeneous treatment setting
not only by sensitivity to previous (neo)adjuvant
chemotherapy, but also according to tumour biology
(depending on priming of the PI3K/AKT signalling
pathway by previous chemotherapy) or clinical features of
recurrence or de-novo stage IV disease that could be
dierentiated by previous (neo)adjuvant chemotherapy.
Placebo tablets were identical in shape and colour to
the ipatasertib tablets. Investigators, patients, and the
sponsor were masked to treatment assignment.
Procedures
Patients received intravenous paclitaxel 80 mg/m² on
days 1, 8, and 15 of each 28-day cycle in combination
with either oral ipatasertib 400 mg/day or placebo,
administered on days 1–21 of each 28-day cycle. There is
no standard paclitaxel schedule in metastatic breast
cancer. Investigators indicated a strong preference for the
3 weeks on/1 week o schedule of paclitaxel 80 mg/m² per
week when the LOTUS trial was designed. This schedule
has been used in previous clinical studies
16,17
and maintains
the cumulative dose intensity achieved with 175 mg/m²
every 3 weeks (as recommended in the prescribing
information). Treatment was continued until disease
progression, intolerable toxicity, or withdrawal of consent.
Ipatasertib or placebo could be temporarily interrupted for
up to 4 consecutive weeks if patients had toxicity
considered related to the study drug. Diarrhoea was
managed with loperamide or according to institutional
guidelines and standard of care, including but not limited
to therapy with diphenoxylate and atropine, codeine,
or octreotide. If symptoms persisted despite adequate
(combination) antidiarrhoeal medications and dose
interruptions, dose reductions were implemented.
Ipatasertib (or placebo) was initially reduced to
300 mg/day, then to 200 mg/day, and was discontinued
permanently at the third appearance of an adverse event
requiring dose reduction. Paclitaxel dose modifications
were implemented according to standard practice or
institutional guidelines. The protocol suggested a
reduction to 65 mg/m² at the first reduction and then
permanent discontinuation if toxicity recurred. All
patients who discontinued study therapy were allowed to
receive subsequent anticancer therapy outside the study
protocol. Disease progression that occurred after initiation
of a new anticancer therapy was not collected per protocol;
in such patients, progression-free survival was censored at
the time of the last tumour assessment.
Tumours were assessed every 8 weeks by the
investigators according to RECIST (version 1.1). After
discontinuation of treatment, patients were followed up
every 3 months for survival and subsequent anticancer
therapies. Safety was assessed and graded according to
National Cancer Institute Common Terminology Criteria
for Adverse Events (version 4.0) on an ongoing basis until
the study drug discontinuation visit (or resolution or
stabilisation of ongoing related adverse events).
Laboratory assessments (including haematology, fasting
serum chemistry, coagulation, fasting lipid profile, and
urinalysis) were done within 48 h before each study drug
admin istration. Patient-reported outcomes (PROs) were
assessed using the European Organisation for Research
and Treatment of Cancer Core Quality of Life
Questionnaire C30 (EORTC QLQ-C30), which includes
30 questions assessing five functional scales, three
symptom scales, and six single items. Questionnaires
were distributed by sta at the site and completed by the
patient before study assessments or drug administration
on day 1 of every cycle, at treatment discontinuation, and
at tumour follow-up. Pharmacokinetic parameters of
ipatasertib were assessed in all patients by sparse plasma
sampling on day 1 of cycle 1 (0·5–2 h and 4–6 h after study
drug administration) and on day 8 of cycle 1 (0–2 h and
2–5 h after study drug administration).
At screening, PTEN status was centrally assessed using
antibody clone 138G6 (cat #9559, Cell Signaling
Technology, Leiden, Netherlands; Targos Molecular
Pathology GmbH, Kassel, Germany). Before the primary
analysis, tumour tissue samples were assessed centrally
by additional molecular assays to define the patient
population with PTEN-low tumours (by immuno histo-
chemistry; co-primary endpoint) and the patient
population with PI3K/AKT pathway-activated tumours
(secondary endpoint). For the co-primary endpoint,
PTEN-low tumours were defined as those having
Articles
www.thelancet.com/oncology Vol 18 October 2017
1363
immunohisto chemistry 0 in at least 50% of tumour cells
using the Ventana immunohistochemistry assay (clone
SP218; Spring Bioscience, Pleasanton, CA, USA). This
assay was used instead of the one used to determine PTEN
status for stratification because it had undergone a greater
degree of technical validation and is being developed as a
potential companion diagnostic assay for ipatasertib. The
classification of PTEN-low tumours also adopted a scoring
method based on quantification of the number of cells
lacking expression, thus providing a more robust scale to
measure the extent of complete loss of PTEN expression.
The FoundationOne next-generation sequencing assay
(Foundation Medicine, Cambridge, MA, USA)
18
was used
to identify patients with PI3K/AKT pathway-activated
tumours, defined as the presence of genetic PTEN-
inactivating alterations or PIK3CA/AKT1-activating
mutations (PIK3CA Arg88Gln, Asn345Lys, Cys420Arg,
Glu542X, Glu545X, Gln546X, Met1043Ile, His1047X, or
Gly1049Arg mutations, where X represents any change in
aminoacid residue, or AKT1 Glu17Lys mutations), referred
to hereafter as PIK3CA/AKT1/PTEN-altered tumours.
Outcomes
The co-primary endpoints were investigator-assessed
progression-free survival in the intention-to-treat
population and progression-free survival in the subgroup
of patients with PTEN-low tumours. Progression-free
survival was defined as the interval between randomisation
and the first occurrence of disease progression or death
from any cause within 30 days of the last dose of study
treatment (death on study). As specified in the protocol,
patients who discontinued study treatment without
documented disease progression were censored at the
date of last tumour assessment before initiation of new
anticancer therapy.
Secondary endpoints were investigator-assessed
confirmed objective response (confirmed by a repeat
assessment at least 4 weeks after the criteria for response
are first met), duration of confirmed objective response
(defined as the interval between first observation of a
confirmed objective response and first observation of
disease progression or death on study as assessed by the
investigator), and overall survival in the intention-to-treat
population and patients with PTEN-low tumours; ecacy
(progression-free survival, confirmed objective response
rate, duration of confirmed objective response, and
overall survival) in patients with PI3K/AKT pathway-
activated tumours; and safety (incidence, nature, and
severity of adverse events). Additional objectives included
assessment of pharmacokinetics; PROs for disease-
related and treatment-related symptoms, patient
functioning, and health-related quality of life; and further
exploratory translational research. We also did post-hoc
analyses of the clinical benefit (defined as either an
objective response, or a best overall response of complete
or partial response or stable disease together with a
progression-free survival of 24 weeks or longer).
Statistical analysis
The planned sample size was 60 patients per group for a
total of 120 patients overall to ensure 83 progression-free
survival events for the primary analysis. As this
hypothesis-generating trial was designed to assess safety
and provide preliminary evidence of activity, it was not
powered to detect minimal clinically meaningful
dierences between treatment groups at a significant
α level of 5%. Instead, 90% CIs for the hazard ratio (HR)
were calculated, anticipating that for clinically
62 received placebo plus paclitaxel
10 treatment ongoing
62 included in intention-to-treat analysis
62 included in intention-to-treat analysis
62 assigned to placebo plus paclitaxel
52 discontinued placebo†
44 disease progression
1 symptomatic
deterioration
1 death
1 adverse event
1 non-compliance
3 patient withdrawal
1 physician decision
61 received ipatasertib plus paclitaxel
16 treatment ongoing
62 assigned to ipatasertib plus paclitaxel
1 received no study
treatment
124 randomly assigned
124 enrolled
166 patients assessed for eligibility
42 ineligible*
45 discontinued
ipatasertib†
36 disease progression
1 symptomatic
deterioration
4 adverse event
3 patient withdrawal
1 physician decision
Figure 1: Trial profile
ECOG=Eastern Cooperative Oncology Group. LVEF=left ventricular ejection fraction. *The reasons for screen
failure in 42 patients were: not meeting inclusion criteria (two signed informed consent, two ECOG performance
status ≤1, one locally advanced or metastatic triple-negative breast cancer not amenable to curative resection,
one measurable disease, and six adequate haematological and organ function), meeting exclusion criteria (one
previous therapy for locally advanced or metastatic triple-negative breast cancer; two radiatiotherapy in previous
28 days; one major surgery, open biopsy, or significant traumatic injury in preceding 30 days; ten known brain or
spinal cord metastasis; one New York Heart Association class II, III, or IV heart failure or LVEF <50%, or active
ventricular arrhythmia requiring medication; one ongoing unstable angina or history of myocardial infarction in
previous 6 months; one grade 3 uncontrolled or untreated hypercholesterolaemia or hypertriglyceridaemia;
three congenital long QT syndrome or screening corrected QT interval ≥480 ms; three inability to comply with
study and follow-up procedures; one other malignancy within 5 years; three potential contraindication); and
12 other reasons (more than one answer possible). †Five patients
in the ipatasertib group and six in the placebo
group received new anticancer therapy after discontinuing study therapy before disease progression. Further
details of patients who discontinued without progression and received new anticancer therapy are provided in
the appendix.
Articles
1364
www.thelancet.com/oncology Vol 18 October 2017
meaningful outcomes, the upper limit of the 90% CI
would be less than 1. We report 95% CIs to be consistent
with published literature. The primary analysis was
intended to include 50 progression-free survival events
in patients with PTEN-low tumours. Assuming
60% prevalence of PTEN-low tumours, we anticipated
83 progression-free survival events in the intention-to-
treat population.
Ecacy analyses were based on all randomly assigned
patients (intention-to-treat population). Analyses for
the co-primary endpoints were stratified; the Cox
proportional hazard model included the treatment group
and three stratification factors as covariates. In this proof-
of-concept study, the definition of progression-free
survival for the primary endpoint was chosen with the
aim of identifying antitumour activity closely related to
Intention-to-treat population PTEN-low population PIK3CA/AKT1/PTEN-altered
tumour population
Ipatasertib
plus paclitaxel
(n=62)
Placebo
plus paclitaxel
(n=62)
Ipatasertib
plus paclitaxel
(n=25)
Placebo
plus paclitaxel
(n=23)
Ipatasertib
plus paclitaxel
(n=26)
Placebo
plus paclitaxel
(n=16)
Median age (years) 54 (44–63) 53 (45–63) 50 (44–63) 56 (46–65) 52 (44–63) 53 (46–60)
Age group
18–40 years 10 (16%) 5 (8%) 4 (16%) 2 (9%) 5 (19%) 1 (6%)
41–64 years 40 (65%) 46 (74%) 18 (72%) 15 (65%) 18 (69%) 14 (88%)
≥65 years 12 (19%) 11 (18%) 3 (12%) 6 (26%) 3 (12%) 1 (6%)
Race
Asian 28 (45%) 30 (48%) 10 (40%) 9 (39%) 16 (62%) 7 (44%)
White 26 (42%) 28 (45%) 12 (48%) 13 (57%) 8 (31%) 9 (56%)
Black or African-American 5 (8%) 3 (5%) 2 (8%) 1 (4%) 0 0
Other 3 (5%) 1 (2%) 1 (4%) 0 2 (8%) 0
ECOG performance status
0 44 (71%) 36 (58%) 17 (68%) 15 (65%) 13 (50%) 9 (56%)
1 18 (29%) 22 (35%) 8 (32%) 7 (30%) 13 (50%) 7 (44%)
Missing 0 4 (6%) 0 1 (4%) 0 0
Previous (neo)adjuvant
chemotherapy*
41 (66%) 40 (65%) 19 (76%) 15 (65%) 18 (69%) 10 (63%)
Anthracycline† 34 (55%) 34 (55%) 16 (64%) 12 (52%) 14 (54%) 7 (44%)
Taxane† 31 (50%) 34 (55%) 18 (72%) 14 (61%) 12 (46%) 7 (44%)
Chemotherapy-free interval (months)*
≤12 18 (29%) 16 (26%) 8 (32%) 4 (17%) 7 (27%) 3 (19%)
>12 23 (37%) 24 (39%) 11 (44%) 11 (48%) 11 (42%) 7 (44%)
None 21 (34%) 22 (35%) 6 (24%) 8 (35%) 8 (31%) 6 (38%)
PTEN H score*
0 10 (16%) 11 (18%) 9 (36%) 7 (30%) 8 (31%) 3 (19%)
1–150 27 (44%) 27 (44%) 10 (40%) 12 (52%) 6 (23%) 6 (38%)
>150 25 (40%) 24 (39%) 6 (24%) 4 (17%) 12 (46%) 7 (44%)
Histopathological subtype‡
Ductal 59 (95%) 59 (95%) 25 (100%) 23 (100%) 24 (92%) 15 (94%)
Lobular 3 (5%) 1 (2%) 1 (4%) 0 2 (8%) 0
Tubular 1 (2%) 3 (5%) 0 0 1 (4%) 1 (6%)
Metastatic sites‡
Lung 27 (44%) 32 (52%) 13 (52%) 14 (61%) 13 (50%) 9 (56%)
Liver 19 (31%) 17 (27%) 7 (28%) 6 (26%) 7 (27%) 5 (31%)
Lymph nodes 36 (58%) 38 (61%) 14 (56%) 18 (78%) 15 (58%) 12 (75%)
Bone 16 (26%) 17 (27%) 7 (28%) 10 (43%) 5 (19%) 8 (50%)
Data are n (%) or median (IQR). ECOG=Eastern Cooperative Oncology Group. IXRS=interactive web-response system. *Stratification factor, reported per IXRS. †Data not from
IXRS. ‡More than one answer possible.
Table 1: Baseline characteristics
