Poor efficacy of palbociclib in second-line treatment of
metastatic lobular breast cancer in a case series: Use before or
never more

Armando Orlandi MD, PhD1 | Francesca Aroldi MD1 | Mattia Garutti MD1 |
Carmela Di Dio MD1 | Giovanna Garufi MD1 | Elena Iattoni MD1 | Antonella Palazzo MD1 |
Giulia Indellicati MD1 | Gianluca Franceschini MD2 | Alessandra Cassano MD1 |
Emilio Bria MD1 | Giampaolo Tortora MD1
1
Unit of Clinical Oncology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy
2
Breast Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy
Correspondence: Armando Orlandi, Unit of Clinical Oncology, Fondazione Policlinico Universitario A. Gemelli IRCCS, L.go F. Vito 1, 00168 Rome, Italy.
Email: [email protected]
Invasive BCs are categorized in two main histological sub￾types: ductal (DC), which represents the majority of BCs, and
lobular (LC), which accounts for only 5%-15%.1
These two histo￾types are classified as separated entities, diversified by biological,
clinical, and pathological features.2
Invasive lobular breast cancer
(ILC) is usually associated with a grim prognosis due to its difficult
clinical and radiological detection, its complex surgical removal,
and its poor response to cytotoxic agents.3
Indeed, ILC is charac￾terized by an infiltrating growth behavior, presenting at histologic
examination as single-cell files or nests of low-grade tumor cells
which invade the surrounding breast tissue.2
This is molecularly
driven by the hallmark loss of expression of E-cadherin (a cell
adhesion protein).4
Moreover, ILC tumor cells display hormonal
receptors (HRs) expression and low to intermediate proliferation
index.2
Hormonal therapy represents the backbone of treatment
of HR-positive metastatic BC (mBC).3
Recently, a new class of
molecules, cyclin-dependent kinase 4/6 inhibitors (CDK4/6i),
proved to improve efficacy of endocrine therapy.5-10 Based on
the results of the PALOMA 2 and PALOMA 3 trials, in 2015 the
FDA approved the combination of palbociclib (a CDK4/6i) plus
letrozole or plus fulvestrant, respectively, for the first- or sec￾ond-line treatment of estrogen receptor positive, HER2-negative
mBC in postmenopausal women. Successively, two other drugs
have been approved and showed efficacy in hormonal naïve and
resistance mBC: ribociclib (MONALEESA trials) and abemaciclib
(MONARCH trials).7-10 While subgroup analysis of PALOMA 2
trial showed that the combination of palbociclib plus letrozole is
effective both in ductal and lobular histotype,5
or even more ac￾tive in the latter, no subgroup analysis is currently available on
the efficacy of CDK4/6i (palbocicilib, ribociclib, and abemaciclib)
in the second-line treatment according to histotype. The intro￾duction into clinical practice of CDK4/6 inhibitors represents a
revolution in the management of HR-positive/HER2-negative BC
patient; however, many questions regarding the optimization of
the therapeutic sequence are still open. In our clinical experience,
we have documented, although in a limited series of clinical cases,
the absence of benefit from such association in the second-line
treatment of patients with metastatic ILC (mILC) refractory to
hormonal therapy. In Table 1, we report biological characteristics
of the four patients affect by mILC with poor performance in term
of PFS of palbocicilib plus fulvestrant in second-line hormonal
setting (3-4 months with progression disease at the first radiolog￾ical revaluation). In three of these cases, patients showed myelo￾toxicity that cause reduction of drug’s dose (from 150 to 100 mg);
however, we have clary acquired that this reduction do not limit
efficacy of this class of drug.5-10 Same results of poor efficacy
of palbociclib plus fulvestrant in hormonal refractory mILC we
found in a recent retrospective multicentric analysis presented
at ESMO congress 2019.11 The lake of efficacy in this setting ap￾pear, in a first approach, not understanding in consideration of
the deep efficacy of this class of drugs that has revolutionized the
treatment of luminal mBC. In fact, the introduction of CDK4/6i
produced a deep improve in the treatment of patients affected by
ER+/HER2- mBC. The significant increase in PFS showed by the
addition of such agents both in first or second line compared to
endocrine monotherapy lead to the fast inclusion of these agents
in the treatment of mBC patients.5-10 However, despite the re￾cent evidence of improving of OS in first line, the apparent lack
of benefit in terms of PFS compared to hormonal monotherapy
in some subgroups5-10 has led to a debate in order to identify the
2  |    COMMENTARY
best therapeutic sequence. These doubts concerning optimal se￾quence are particularly pronounced in the setting of ILC. Given
the limited chemosensitivity of such disease, an optimized hor￾monal sequence represents the treatment with the greatest im￾pact on survival.3
The efficacy of CDK4/6i, which carry out their
efficacy limiting the cell cycle by inhibiting cyclin D (Figure 1),
has clearly been shown in front line in metastatic ILC, whereas it
has not been explored and confirmed in the second-line setting in
registration studies.5-10 In our clinical experience, we have docu￾mented the absence of benefit from such association in the sec￾ond-line treatment of patients with mILC. Such negative evidence
might be explained by the differential molecular pathway activi￾ties between ductal and lobular disease. Indeed, CDH1 mutations
represent a specific molecular hallmark of ILC and are associated
with elicitation of EGFR and AKT pathways.1
Moreover, many
ILCs show activating mutations of FGFR pathway.12 Given such
evidences, we postulate that in ILCs acquired endocrine resis￾tance might be associated with overexpression of EGFR, AKT, and
FGFR pathway, causing proliferation and bypassing drug blockage
and efficacy of CDK4/6i. In lobular carcinomas, the dysregulation
of the AKT pathway is very often the main mechanism of resis￾tance to hormone therapy.1
As recently demonstrated in some in
vitro studies, this dysregulation could lead to the amplification
of cyclin E favoring the division and grow of the neoplastic cell.13
This mechanism of resistance to hormone therapy would imply an
intrinsic mechanism of resistance to therapy with CDK4/6i over￾coming the blockade of cyclin D (Figure 2). These considerations
are currently only a hypothesis, but they allow us to explain the
possible lack of efficacy of CDK4/6i after resistance of hormonal
therapy was acquired. Although the biological and metastatic
diffusion differences between ILC and IDC are known,a similar
treatment is recommended from the principal oncologic guide￾lines for a lack of specific evidence for each histotype. Metastatic
ILC represent a minority of breast cancer that need a specific and
addressed clinical trial to understand the best practice to ap￾proach this disease.
Attending more specific and prospective evidence, given such
hypothesis, administration of CDK4/6i could be preferred to the
first-line treatment of ILCs, privileging combination with mTOR in￾hibitors in the second-line treatment.
TABLE 1 Molecular characteristic of patients and hormonal therapy efficacy
46 (DFS) Fulv + Pal 4 Yes
Abbreviations: DFS, disease-free survival; Fulv, fulvestrant; Pal, palbociclib; PFS, progression-free survival; Tam, tamoxifen; Trip, triptorelin.
FIGURE 1 In ILC naive for hormonal
therapy, estrogen receptor pathway is
one of the main signals that stimulate the
cell cycle progression through the cyclin
D-CDK4/6 complex formation and the RB
phosphorylation (transition from phase G0
to G1 of cell cycle). In this context, a CDK
4/6 inhibitor might block the proliferation
of cancer cells by impairing the growth of
neoplastic cell
   | COMMENTARY  3
CONFLICT OF INTEREST
The authors have no relevant affiliations or financial involvement
with any organization or entity with a financial interest in or financial
conflict with the subject matter or materials discussed in the manu￾script. This includes employment, consultancies, honoraria, stock
ownership or options, expert testimony, grants or patents received
or pending, or royalties. No writing assistance was utilized in the pro￾duction of this manuscript.
ETHICAL APPROVAL
The authors state that they have obtained appropriate institutional
review board approval or have followed the principles outlined in the
Declaration of Helsinki for all human or animal experimental inves￾tigations. In addition, for investigations involving human subjects,
informed consent has been obtained from the participants involved.
ORCID
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How to cite this article: Orlandi A, Aroldi F, Garutti M, et al. Poor
efficacy of palbociclib in second-line treatment of metastatic
lobular breast cancer in a case series: Use before or never more