Fulvestrant and trastuzumab in patients with luminal HER2‑positive
advanced breast cancer (ABC): an Italian real‑world experience
(HERMIONE 9)
Rosalba Torrisi1 · Rafaella Palumbo2 · Rita De Sanctis1,3 · Patrizia Vici4 · Giulia Valeria Bianchi5
Laura Cortesi6
· Vita Leonardi7 · Rossana Gueli8 · Alessandra Fabi9 · Maria Rosaria Valerio10 ·
Anna Rita Gambaro11 · Barbara Tagliaferri2 · Laura Pizzuti4
· Marina Elena Cazzaniga12 · Armando Santoro1,3
Received: 11 May 2021 / Accepted: 20 August 2021
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021
Abstract
Purpose The most appropriate therapy for HR+/HER2-positive (HER2+) advanced breast cancer (ABC) is a matter of
debate. Co-targeting of both receptors represents an attractive strategy to overcome the cross-talk between them.
Methods The HERMIONE 9 is an observational retrospective multicentric study which aimed to describe the clinical outcome of patients with HR+/HER2+ABC who received the combination of Fulvestrant (F) and Trastuzumab (T) as part of
their routine treatment at 10 Italian Institutions.
Results Eighty-seven patients were included. Median age was 63 (range, 35–87) years. The median number of previous
treatments was 3 (range, 0–10) and F and T were administered as≥3rd line in 67 patients. Among the 86 evaluable patients,
6 (6.9%) achieved CR, 18 (20.7%) PR, and 44 (50.6%) had SD ≥24 weeks with an overall CBR of 78.2%. At a median
follow-up of 33.6 months, mPFS of the entire cohort was 12.9 months (range, 2.47–128.67). No diference was observed
in mPFS between patients treated after progression or as maintenance therapy (mPFS 12.9 and 13.9 months in 64 and 23
patients, respectively), neither considering the number of previous treatment lines (≤3 or<3).
Conclusion The combination of F and T was active in this cohort at poor prognosis and deserves further investigations possibly in combination with pertuzumab in patients with high ER expression.
Keywords Trastuzumab · Fulvestrant · Hormone receptor positive · HER2 positive · Advanced breast cancer
* Rosalba Torrisi
[email protected]
1 Department of Medical Oncology and Hematology Unit,
IRCCS Humanitas Research Hospital, via A. Manzoni 56
20089, Rozzano, Milano, Italy
2 Oncologia Medica, IRCCS ICS Maugeri, Pavia, Italy
3 Department of Biomedical Sciences, Humanitas University,
Pieve Emanuele, Italy
4 UOC OM2 IRCCS Regina Elena National Cancer Institute,
Roma, Italy
5 SC Oncologia Medica 1 Fondazione IRCCS Istituto
Nazionale Tumori, Milano, Italy
6 Department of Oncology and Haematology, Modena
Hospital University, Modena, Italy
7 Department of Medical Oncology, ARNAS Civico, Palermo,
Italy
8 Medical Oncology, ASST Settelaghi, Varese, Italy
9 Precision Medicine in Breast Cancer Unit, Scientifc
Directorate, Fondazione Policlinico Universitario A. Gemelli,
IRCCS, Rome, Italy
10 Medical Oncology Unit, Department of Surgical,
Oncological and Oral Sciences, University of Palermo,
Palermo, Italy
11 Medical Oncology, ASST Fatebenefratelli Sacco PO Sacco,
Milano, Italy
12 Centro Ricerca Fase 1 ASST Monza and Università Degli
Studi Milano Bicocca, Milano, Italy
Breast Cancer Research and Treatment
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Introduction
Gene expression studies have clearly demonstrated in
recent years that HER2-positive (HER2 +) breast cancer
is a heterogeneous disease [1]. Approximately, 50% of
HER2+tumors are hormone receptor positive (HR +) at
immunohistochemistry (IHC) [2]
However, only one half of HER2+tumors at IHC correspond to the HER2-enriched subtype as defned by gene
expression profling, and within the latter subtype signifcant molecular diferences were observed according to the
HR expression [3]
However, these immunohistochemical and molecular
diferences do not translate in diferent therapeutic strategies for treatment of HR+/HER2+tumors which routinely
include chemotherapy and anti-HER2 agents [4]. Preclinical evidence suggesting that HER2 overexpression was
associated with endocrine resistance [5], further confrmed
by the poor results of earlier studies investigating a chemotherapy-free regimen in advanced HR+/HER2+tumors
[6, 7], supported an unique treatment strategy including
chemotherapy plus anti-HER2 therapy irrespective of HR
status [5]. However, results from neoadjuvant trials and
from the advanced setting clearly indicated less sensitiveness of luminal HER2+tumors to this approach probably
due to a bidirectional cross-talk between the two driver
receptors, estrogen and HER2 [8–11]. Co-targeting of both
receptors appears thus an attractive strategy to overcome
the resistance due to this cross-talk [12].
The availability of fulvestrant which internalizes ER
after binding, leading to a more complete abolishment of
the estrogen signaling with respect to aromatase inhibitors,
might represent an attractive targeted partner for a full HR/
HER2 blockade [13]. A synergistic efect between fulvestrant and trastuzumab in inhibiting growth in cell lines and
xenografts has been shown, but only a few in vivo data are
available on the combination [14].
In the present retrospective observational study
we report a real-world series of patients with HR + /
HER2 + advanced breast cancer (ABC) treated with the
combination of fulvestrant and trastuzumab and analyze
possible predictive factors of its efectiveness.
Patients and methods
The HERMIONE 9 is an observational retrospective multicentric study which aimed to describe the clinical outcome of patients with HR+/HER2+ ABC who received
the combination of fulvestrant and trastuzumab as part of
their routine treatment at 10 Italian Institutions participating to the HERMIONE platform.
Eligible patients were pre- and postmenopausal women
aged≥18 years diagnosed with HR+(defned as ER and/
or PgR≥10%) and HER2+(defned as IHC 3+or FISH or
CISH or SISH positive) inoperable locally advanced and/or
metastatic breast cancer. Premenopausal patients received
concomitant ovarian suppression with GnRH analogues.
Fulvestrant+trastuzumab were administered as any line
of treatment. Fulvestrant was administered 500 mg i.m.
q28 days with loading dose after 14 days; trastuzumab was
administered q21 days either as 8 mg/kg loading dose and
then 6 mg/kg i.v. infusion or 600 mg s.c., according to the
internal institutional guidelines.
Patient medical charts were reviewed and tumor response
was assessed. Since this is a retrospective study response
could not be evaluated according to RECIST 1.1 criteria in
all patients, but CT scans and other imaging were reviewed
in order to comply with RECIST criteria whenever possible.
Information on age at diagnosis, menopausal status, previous adjuvant therapies, number of previous therapies for
metastatic disease, number and response to previous therapies for metastatic disease, pathological features of primary
and metastatic tumor if available, sites of metastatic disease,
best response, and disease progression if occurred, and last
follow-up visit were collected.
This study was approved by the institutional ethical committee of the coordinating center (Humanitas Research Hospital) and of all the other participating Institutions and was
conducted in compliance with Helsinki Declaration.
Statistical analysis
Clinical data were summarized as frequencies and proportions or as medians and range. To assess the tumor heterogeneity, we calculated the agreement in the tumor biological profle between primary and metastatic sites in terms of
ER, PgR, and HER2 expression using Cohen’s K statistics.
Response to treatment was classifed as complete response
(CR), partial response (PR), stable disease (SD), or progressive disease (PD) according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.1
whenever possible. Clinical Beneft Rate (CBR) was defned
as the percentage of patients who achieved CR, PR, and
SD ≥24 weeks. Survival curves were estimated using the
Kaplan–Meier method. Progression-Free Survival (PFS) was
defned as the time from the frst day of fulvestrant+trastuzumab until disease progression, as shown by radiological
or clinical examination, or death from any cause. Patients
without any evidence of progressive disease were censored
at the date of their last follow-up. PFS curves were analyzed
according to disease status at fulvestrant+trastuzumab start,
early versus later fulvestrant+trastuzumab line of treatment,
the type of previous therapy, and HR status. Diferences
among subgroups were evaluated using the log-rank test.
Statistical signifcance was set at 0.05. Analyses were performed with the STATA software package, version 15 and
with STATISTICA version 7, StatSoft, Inc.
Results
From August 2005 to March 2021 a total of 87 patients were
treated with the combination of fulvestrant+trastuzumab at
the 10 participating Institutions.
Median age was 63 years (range, 35–87). Clinical pathological patients’ characteristics are reported in Table 1.
Thirty-one percent (27/87) of the patients were diagnosed
with de novo metastatic breast cancer; in recurrent ABC
(60/87, 69%), median time to metastatic disease was
57.1 months (range, 7.0–330.5).
A biopsy of metastatic site was available in 48 out of
87 patients (45.9%); biological characteristics of metastases were concordant with those of primary tumors except
for PgR expression which was signifcantly lower (p=0.02)
As a consequence, 59 patients (67.8%) had triple-positive
tumors as determined in the primary tumor while in metastatic biopsies only 22 /45 (49%) metastatic tumors were
triple positive.
The median number of previous treatments (both chemotherapy±trastuzumab and endocrine therapy+trastuzumab)
for advanced disease was 3 (range, 0–10). Fulvestrant+trastuzumab were administered as≥3 line in 67 patients. All
patients had received trastuzumab previously while only
19% of patients had not received prior endocrine therapy
for ABC.
Twenty-three patients started fulvestrant+trastuzumab
as maintenance treatment while 64 patients had progressed
upon the previous regimen (20 patients after endocrine
therapy+trastuzumab, 22 after anti-HER2 agents+chemotherapy, and 20 after chemotherapy).
The median duration of fulvestrant+trastuzumab treatment was 11.5 months (range, 2.03–128.67). Trastuzumab
was administered i.v. (57/87, 65.52%), or s.c. (15/87,
17.24%), or both (11/87, 12.64%); the data were not available in 4 cases.
Eight-six patients were evaluable for response: 6
patients achieved CR (6.9%), 18 patients (20.7%) PR, and
51 patients (58.6%) SD—of whom 44 patients (50.6%) had
SD≥24 weeks. Overall, the CBR was 78.2%. At a median
follow-up of 33.6 months (range, 2.47–139.27), mPFS of the
entire cohort was 12.9 months (range, 2.47–128.67; Fig. 1).
A shorter time to progression (TTP) was observed during the
treatment immediately preceding fulvestrant+trastuzumab
(7.62 months, range, 2.0–98.9). No statistically signifcant
diference was observed in mPFS in patients treated after
Table 1 Baseline patient and disease characteristics
Median age, years (range) 63 (35–87)
De novo mBC, n (%) 27 (31.03)
Menopausal status, n (%)
Pre-menopausal 24 (27.59)
Post-menopausal 60 (68.96)
Unknown 3 (3.45)
progression to a previous line or as maintenance (mPFS
12.9 and 13.9 months, respectively; p=0.67), neither considering the number of previous treatment lines (≤3 or<3)
(p=0.34), the type of previous therapy (chemotherapy or
endocrine therapy), or triple positive vs single HR expression overall (p=0.22).
Discussion
In the era of tailored treatments the most appropriate therapy
of HR+/HER2+BC is a matter of debate. While showing
less responsiveness to the combination of chemotherapy
plus anti-HER2 agents as compared to the HR negative
counterpart, results with the combination of anti-HER2
agents and non-steroidal aromatase inhibitors (NSAI)
have been quite disappointing with a mPFS not exceeding
4.8 months with trastuzumab and anastrozole and 8.2 months
with lapatinib and letrozole as frst-line treatment [6, 7]. The
recently updated ALTERNATIVE trial, which investigated
the addition of lapatinib, trastuzumab, or both agents to a
NSAI, showed a signifcant improvement in mPFS for the
double HER2 blockade vs trastuzumab plus NSAI (11 vs
5.6 months) [15]. On the other hand the PERTAIN trial
reported a mPFS of 21.7 months in the arm with the double HER2 blockade with pertuzumab and trastuzumab plus
a NSAI, which was not only signifcantly higher than that
reported by the trastuzumab plus NSAI combination but,
more importantly, was similar to that reported in patients
who had received chemotherapy before endocrine therapy
(mPFS=18.9 months) [16]. The relative small number of
patients (54) and the non-randomized assignment to the
chemotherapy/no chemotherapy arms leading to a smaller
proportion of patients with poor prognostic features in the
latter arm, do not allow to qualify the chemotherapy-free
combination as a standard frst-line treatment for HR+/
HER2+ ABC, but clearly represents a strong rationale for
further studies to identify which patients may be spared
unnecessary chemotherapy [16].
Fulvestrant was proven superior to NSAI in patients
with HR + /HER2—ABC [17] and has been considered
as favorite anti-ER partner in combination with other targeted therapies in HR+/HER2+breast cancer (Na-PHer2,
MonarcHER), despite the lack of clinical data of the activity of this combination [18, 19]. Fulvestrant monotherapy
showed an encouraging activity in a retrospective study in
102 pretreated patients with HR+/HER2+ABC with a CBR
of 42% and a median duration of treatment of 8.1 months,
which raised to 14.5 months in patients achieving clinical
beneft. Among them only 5 patients had received concurrent trastuzumab [20]. Bartsch et al. reported outcomes of
112 patients with HR+tumors treated with Fulvestrant 20
of whom had HR+/HER2+tumors and HER2 status did not
predict treatment efcacy [21]. Rusz et al. reported a durable
beneft (12, 25, and 28 months) with Fulvestrant monotherapy in 3 pretreated patients with triple-positive ABC [22].
The SystHER, an observational prospective registry study
reporting tumor characteristics, treatment patterns, and outcome of patients with HER2+ABC treated in the USA from
2012 to 2016, included 46 patients who received Fulvestrant
but no further information on the setting and outcome is
available yet [23].
To our knowledge this is the frst report of the combination of fulvestrant+trastuzumab in a clinically relevant number of patients. We observed a mPFS of 12.9 months and a
CBR of 78% which favorably compare with those previously
reported by the combination of a NSAI and trastuzumab
HR hormone receptor, ER estrogen receptor, PgR progesterone receptor, CT chemotherapy, ET endocrine therapy, F fulvestrant, T trastuzumab
Table 1 (continued)
Median age, years (range) 63 (35–87)
Prior lines of therapy ET, n (%)
0 16 (18.39)
1 51 (58.62)
2 17 (19.55)
3 3 (3.44)
Last treatment before F+T, n (%)
CT+trastuzumab 23 (26.43)
ET+trastuzumab 20 (22.99)
T DM1 8 (9.20)
Lapatinib+capecitabine 4 (4.60)
CT 12 (13.79)
Trastuzumab 1 (1.15)
ET 10 (11.49)
Clinical trial 1 (1.15)
Unknown 8 (9.20) 0.00 0.25 0.50 0.75 1.00 Survival probability
0 50 100 150
Time (months)
Progression-Free Survival
Fig. 1 Progression-free survival in the overall population
Breast Cancer Research and Treatment
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even when administered in earlier lines [6, 7, 15, 16]. Only
the addition of pertuzumab gained a superior mPFS in the
PERTAIN study [16]. As expected, our results favorably
compare also with those obtained with single agent Fulvestrant, particularly in terms of CBR [20–22].
Remarkably, 77% of our patients had been treated with≥3
previous therapies for metastatic disease, 73% started fulvestrant+trastuzumab after progression to a previous regimen, and more than 50% had visceral disease. The short
TTP (7.5 months) observed with the treatment preceding
the fulvestrant+trastuzumab combination confrms that our
unselected population represented a really poor prognosis
cohort.
Fulvestrant was administered as frst-line endocrine therapy only in 19% of patients but its activity did not seem to be
afected by prior endocrine resistance since the patients (20)
who had progressed on endocrine therapy+trastuzumab had
a mPFS of 14.26 months (4.37–119.93), thus maintaining
responsiveness to a diferent endocrine manipulation. On the
other hand, also patients progressing after a chemotherapy
containing regimen experienced an mPFS of 12.73 months
(range 3.07–59.57); in both cohorts the mPFS was signifcantly longer than the TTP obtained with the preceding therapy underlining the activity of the combination irrespective
of prior treatments.
Despite the beneft of endocrine maintenance therapy
has not been formally investigated in a randomized trial,
evidence from PERTAIN and real-world reports support
the efcacy of a sustained blockade of the ER signaling in
HR+/HER2+breast cancer [25, 26]. Our results reporting a
mPFS of 13.9 months in patients who received maintenance
fulvestrant are in line with these reports.
Interestingly, in our study triple-positive tumors did not
fare better than single HR-positive tumors. Triple-positive
breast cancer, which accounts for 5–10% of all breast cancers, might represent a distinct subtype among luminal
HER2 breast cancer with more exquisite endocrine sensitiveness. [27]. However, triple-positive breast cancer has
been described as a heterogeneous population. A genomic
analysis of 5 cohorts of triple-positive breast cancer showed
lower levels of HER2 mRNA and protein expression than
ER and PgR positive/HER2+breast cancers. More than 40%
of triple-positive breast cancers were classifed as the luminal A intrinsic subtype, with an even lower HER2 expression level and were associated with a better prognosis and a
reduced beneft from trastuzumab [28]
In a large retrospective series of 872 patients Vici et al.
showed a signifcant interaction between HR expression and
trastuzumab beneft since patients with triple positive tumors
and HR>50% gained a modest beneft from adjuvant antiHer2 treatment [29]. In our series ER status maintained a
predictive role, while PgR was not associated with response.
The loss of PgR, which may be also attributable to previous
endocrine treatment, apparently did not represent a feature of
endocrine resistance, as suggested by its lower expression in
metastatic sites without afecting treatment efcacy.
A reduced beneft of the combination of chemotherapy
and trastuzumab in the adjuvant setting was shown in a retrospective analysis of the National Cancer Database among
37777 stage I luminal HER2+breast cancer. A large proportion had received only the combination of endocrine therapy
and trastuzumab and had an improved overall survival as
compared with patients who were treated with chemotherapy
and trastuzumab [30].
Fulvestrant has been chosen as preferred endocrine partner in combination with anti-HER2 agents and CDK4/6
inhibitors either in the early and advanced setting [18, 19],
In the phase II Na-PHER2 study the combination of pertuzumab, trastuzumab, fulvestrant, and palbociclib achieved
an objective response and a pathological complete response
in 97 and 27% of patients with large HR+/HER2+tumors,
respectively [18].
The MonarcHER study randomized the combination of
fulvestrant, trastuzumab and abemaciclib vs trastuzumab,
and abemaciclib vs trastuzumab plus chemotherapy in heavily pretreated HR+/HER2+ABC [19]. The triple targeted
regimen resulted in a mPFS of 8.3 months signifcantly
higher than that obtained with chemotherapy, suggesting a
beneft of the addition of the blockade of the CDK4/6 pathway. The lack of an arm containing fulvestrant and trastuzumab has represented the major criticism to these results
since this did not allow to evaluate the net beneft of the
CDK4/6 inhibitor.
These results, along with other indirect evidence, suggest
that at least a proportion of luminal HER2+breast cancer
may experience a favorable outcome without chemotherapy.
We are aware of several limitations of our real-world
study as compared with prospective trials. First of all the
retrospective design which may have not allowed to meet
with a strict application of RECIST 1.1 criteria in all the
patients. In addition the majority of our patients had not
received pertuzumab in earlier lines and this may have led
to the inclusion of a relatively less resistant cohort. Finally,
given the multicentric design, the sequence of treatments
varied among the diferent Hospitals and might have interfered with the results obtained especially with the defnition
of predictive factors of efcacy.
Despite these limitations, our results provide a piece
of evidence in the refnement of the optimal treatment of
HR+/HER2+breast cancer. Our results suggest that the
combination of fulvestrant and trastuzumab is active and
may deserve further investigations, possibly in combination
with pertuzumab and in patients with high ER expression.
Patients with de novo HR+/HER2+ ABC, who represent
30% to 50% of patients receiving frst-line treatment, generally experience better outcome as compared with those
Breast Cancer Research and Treatment
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with recurrent ABC [24]. For instance, it would be interesting to test this combination±CDK4/6 inhibitors vs the
chemotherapy containing triplet in this population at better
prognosis to understand whether the algorithm of treatment
of HER2+breast cancer may be tailored according to the
HR status.
Acknowledgements The authors are indebted with Dr Elisa Crotti for
her invaluable support in the realization of the study.
Author contributions All authors contributed to the study conception
and design. Material preparation, data collection, and analysis were
performed by RT, RP, RdS, PV, GB, LC, VL, RG, AF, MRV, ARG,
BT, and LP. The frst draft of the manuscript was written by RT and
all authors revised all the versions of the manuscript. All authors read
and approved the fnal manuscript.
Funding The authors did not receive any fnancial support.
Data availability The datasets generated during and analyzed during
the current study are available from the corresponding author on reasonable request.
Declarations
Conflict of interest Rosalba Torrisi: Astra Zeneca, Eisai, Pfzer, Eli
Lilly, and Gentili. Rita De Sanctis Novartis, Amgen, Kyowa Kirin,
and Eisai. Patrizia Vici: Roche, Pfzer, Novartis, Gentili, Eli Lilly,
and Eisai. Giulia Valeria Bianchi: Eli Lilly and Novartis. Laura Cortesi: Novartis, Amgen, Astra Zeneca, and Pfzer. Laura Pizzuti Roche,
Pfzer, Novartis, Gentili, and Eisai. Marina Elena Cazzaniga: Astra Zeneca, Novartis, Eli Lilly, Eisai Pierre Fabre, and Roche. Armando Santoro BMS, Servier, Gilead, Pfzer, Eisai, Bayer, MSD, Takeda, Roche,
Astra Zeneca, Pfzer, Eli Lilly, Novartis, Aqule, Sandoz, and Abb-Vie.
Ethical approval The study was approved by the Ethical Committees of
all the participating Institutions. The study was conducted in compliance with Helsinki Declaration.
Consent to participate All patients provided written consent for the use
of their anonymized clinical data for scientifc purpose.
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