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\begin{document}

\title{A rare case of metaplastic breast carcinoma from India: Towards
precision oncology}



\author[1]{Soirindhri Banerjee}%
\author[2]{Ishika Mahajan}%
\author[3]{Aruni Ghose}%
\author[4]{Stergios  Boussios}%
\author[1]{Shivam Chakraborty}%
\affil[1]{IPGMER}%
\affil[2]{Lincoln County Hospital}%
\affil[3]{Barts Health NHS Trust}%
\affil[4]{Medway NHS Foundation Trust}%


\vspace{-1em}



  
  \date{May 25, 2024}


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\selectlanguage{english}
\begin{abstract}
Background : Metaplastic Breast Cancer (MpBC) is an exceedingly rare
entity, accounting for less than 1\% of all malignant breast tumours.
Predominantly triple-negative, they are notorious for their
chemoresistance, high rates of recurrence and decreased disease-free
survival (DFS). All this contributes significantly to BC mortality and
results in poor prognostic implications. Limited evidence has led to a
lacuna of specific treatment guidelines for this entity and hence
remains an uncharted territory for clinicians. Case : We report a case
of left-sided low-grade metaplastic triple negative T3N2aM0 BC treated
with neoadjuvant chemotherapy, primary surgery, and adjuvant
radiotherapy, presently in remission. Conclusion : Limited experience in
management of this pathological entity warrants the need for more
research on it, with a special focus on targeted therapy. Discussing
possibilities of a tailored approach, rather than a one-size-fits-all
approach may aid in paving the path for the future of MpBC treatment.%
\end{abstract}%



\sloppy


\textbf{Title :}

\textbf{A rare case of metaplastic breast carcinoma from India: Towards
precision oncology}

\textbf{Authors:}

\textsuperscript{\textbf{*}}\textbf{Soirindhri
Banerjee\textsuperscript{1}, Ishika Mahajan\textsuperscript{2}, Aruni
Ghose\textsuperscript{3,4,5,6,7}, Stergios
Boussios\textsuperscript{5,8,9,10}, Shivam
Chakraborty\textsuperscript{11}}

\textsuperscript{1}Department of Radiation Oncology, Institute of Post
Graduate Medical Education \& Research and SSKM Hospital, Kolkata,
India.

\textsuperscript{2}Department of Haematology and Oncology, Lincoln
County Hospital, United Lincolnshire Hospitals Trust, Lincoln LN2 5QY

\textsuperscript{3}Department of Medical Oncology, Barts Cancer Centre,
St. Bartholomew's Hospital, Barts Health NHS Trust, London, UK

\textsuperscript{4}Department of Medical Oncology, Mount Vernon Cancer
Centre, East and North Hertfordshire NHS Trust, London, UK

\textsuperscript{5}Department of Medical Oncology, Medway NHS Foundation
Trust, Kent, UK

\textsuperscript{6}United Kingdom and Ireland Global Cancer Network

\textsuperscript{7}Immuno-Oncology Clinical Network, UK

\textsuperscript{8}Faculty of Life Sciences and Medicine, School of
Cancer and Pharmaceutical Sciences, King's College London, London, UK

\textsuperscript{9}Kent and Medway Medical School, University of Kent,
Canterbury, UK

\textsuperscript{10}AELIA Organisation, 9th Km Thessaloniki -- Thermi,
57001, Thessaloniki, Greece

\textsuperscript{11}Depatment of Pathology, Institute of Post Graduate
Medical Education \& Research and SSKM Hospital, Kolkata, India.

*\textbf{Corresponding Author}

Soirindhri Banerjee

Senior Resident

Department of Radiation Oncology, Institute of Post Graduate Medical
Education \& Research and SSKM Hospital.

244, A J C Bose Road, Kolkata 700020, India.

Email -- soirindhribanerjee@yahoo.co.in

\textbf{Abstract~}

\textbf{Background :} Metaplastic Breast Cancer (MpBC) is an exceedingly
rare entity, accounting for less than 1\% of all malignant breast
tumours. Predominantly triple-negative, they are notorious for their
chemoresistance, high rates of recurrence and decreased disease-free
survival (DFS). All this contributes significantly to BC mortality and
results in poor prognostic implications. Limited evidence has led to a
lacuna of specific treatment guidelines for this entity and hence
remains an uncharted territory for clinicians.

\textbf{Case :} We report a case of left-sided low-grade metaplastic
triple negative T3N2aM0 BC treated with neoadjuvant chemotherapy,
primary surgery, and adjuvant radiotherapy, presently in remission.

\textbf{Conclusion :} Limited experience in management of this
pathological entity warrants the need for more research on it, with a
special focus on targeted therapy. Discussing possibilities of a
tailored approach, rather than a one-size-fits-all approach may aid in
paving the path for the future of MpBC treatment.

\textbf{Keywords}

breast cancer; metaplastic; triple negative; adjuvant radiotherapy;
targeted therapy

\textbf{Introduction}

A rare entity, constituting 0.2-5\% of the global breast cancer (BC)
burden, metaplastic breast cancer (MpBC) {[}1{]}.~ MpBC represents a
significant proportion of global BC mortality.

MpBC represents a group of mostly high-grade tumours, demonstrating at
least two unique cellular types- characteristically epithelial and
mesenchymal elements mixed with carcinoma of the usual kind {[}2{]}.
These metaplastic changes represent a conversion from glandular breast
tissue to non-glandular carcinomatous (squamous) and sarcomatous
(spindle cell, chondroid, osseous, and rhabdoid cells) morphologies
{[}3{]}.

There can be high-grade variants with high metastasis potential or
low-grade variants such as fibromatosis-like carcinoma and low-grade
adenosquamous carcinoma (Fig 1).

The high-grade variants have a high likelihood of metastasis and are
notoriously chemoresistant and aggressive {[}4{]}. The rarer low-grade
variants have a relatively favourable prognosis as compared to the
commoner high-grade subtypes {[}5{]}.

These tumours are typically triple-negative {[}3,4{]}. There are however
proteomic and genomic differences between conventional TNBC and MpBC.
Spindle-cell carcinoma commonly expresses p63 and low-grade
adenosquamous carcinoma show high rates of PIK3CA. Conventional TNBC
have low PIK3CA expression. Osteoid and chondroid variants show
increased SNail, BCL-2-like protein and Akt-1 pathway activity. In
contrast to non-MpBC TNBC tumours, MpBC showed higher upregulation of
epithelial-to-mesenchymal transition (EMT) and collagen genes, but
downregulation of keratinization genes. These support the hypothesis
that the histological, proteomic and genomic variations may contribute
to the deadliness of these BC variants {[}6{]}.

MpBC has a worse prognosis as compared to non-metaplastic
triple-negative BC (TNBC). There is a shorter disease-free interval and
overall survival with a double chance of recurrence {[}7{]}. Spindle
cell differentiation has the worst 5-year survival at about 40\%
{[}6{]}.

Here we report the case of a lady who presented with a locally advanced
disease that was found to be metaplastic cancer on histology and is now
3 years disease free.

\textbf{Case}

A 46-year-old premenopausal, diabetic lady with two living children
presented to the outpatient clinic in September 2020 with a left-sided
breast lump.

On clinical examination, the lump measured 5x6 cm, occupying the upper
half of the left breast. It extended to the nipple-areolar complex (NAC)
with no fixity to the skin or underlying tissue. There were no skin
changes. Axillary palpation showed multiple left-sided matted lymph
nodes.

Elaboration of a risk factor history revealed a 5-year history of oral
contraceptive pills (OCPs) usage 20 years previously.

An Ultrasonogram of the breasts showed a large hypoechoic
space-occupying lesion, measuring about 6.5x4.6cm, with irregular,
mildly lobulated margins on the left upper breast at 12 o'clock
position. The lesion showed no calcification or necrosis. Two oval lymph
nodes measuring 1.2cm and 1.4cm in the largest diameter with noted in
the left axilla. The scan was classified as BIRADS-4.

A trucut biopsy was done shortly after the presentation. The
histopathology of the sample was suggestive of invasive BC.
Immunohistochemistry (IHC) revealed hormone receptors (oestrogen and
progesterone) and HER2-neu negative- triple negative breast cancer
(TNBC).

Oncological work-up including a chest X-ray (CXR) and USS of her abdomen
revealed no abnormalities. A Tc99 m bone scan was advised, but the
patient was unable to get it done due to economic constraints.

The tumour was staged at T3N2aM0 and the patient was discussed in a
multidisciplinary team meeting. She was planned for surgical clip
(marker) placement to delineate the tumour margins followed by
neoadjuvant chemotherapy (NACT), re-imaging and definitive surgery. A
further plan was to be made following the histopathological examination
of the surgical specimen.

She underwent 6 cycles of NACT with intravenous Docetaxol (75mg/m2),
Doxorubicin (50mg/m2) and Cyclophosphamide (500mg/m2) at 3 weekly
intervals. Chemotherapy was tolerated well.

An interval ultrasonogram of both breasts was done post-chemotherapy,
which showed an interval increase in the size of the lesion-
9.4x6.4x5.9cm. There were internal echoes noted, likely necrotic foci
within the lesion, with no significant axillary adenopathy. The right
breast remained normal. The scan was classed BIRADS-6.

Following this, the option of surgery was discussed with the patient.
She was keen on breast conservation. Due to a high breast: tumour ratio,
she underwent a left-sided extreme oncoplasty- where the tumour and left
axillary nodal tissue were removed en-mass and reconstruction was
performed with a latisimus dorsi musculocutaneous flap. The
nipple-areola complex was spared. The post-operative period was
uneventful.

Histopathological sections of the 18x13x6cm surgical specimen showed a
tumour measuring 7x6x4 cm. The tumour was composed of tubules, clusters,
solid nests, and syncytial cell infiltrate. (Fig 2) A large necrotic
focus was also identified. There were areas of mesenchymal
differentiation with pleomorphic cells and intervening occasional
spindle cells. The cells had a variegated appearance and showed
pleomorphism, prominent nucleoli and brisk mitosis. There was no
evidence of lymphovascular or perineural invasion and no component of
ductal carcinoma in situ. All resection margins and deep margins were
clear. All resected axillary lymph nodes were negative. The tumour was
classified as Grade 3, staged pT3N0Mx.

She was rediscussed in the multidisciplinary team meeting. The meeting
outcome was to treat her with adjuvant radiotherapy (RT) utilizing
external beam RT (EBRT) with a Telecobalt-60 machine (42.6 Gray in 16
fractions) with photon boost to the surgical bed, marked by the initial
clips placed (10 Gray in 5 fractions) using right and left tangential
fields. In June 2021, she completed EBRT uneventfully. Since then, she
has been on 3 monthly follow-up visits with USS of bilateral breast and
axillae, serum CA15-3 level and clinical breast examination alongside CT
scan of thorax done 6 monthly. None of the aforesaid modalities have
shown evidence of residual or recurrent disease and she has had no fresh
complaints.

\textbf{Discussion}

Metaplastic breast cancer is an infrequent cancer of the breast, the
identification, elucidation and management of which is an evolving
field, gaining momentum over the last two decades {[}8{]}.

The median age of presentation is 48-59 years i.e. perimenopausal women.
{[}9{]}\textbf{~} Earlier database analyses have shown a higher mean age
of diagnosis of 61 years. {[}10{]} Our patient did not fit this
demographic, with a younger age of presentation and pre-menopausal
status. A higher prevalence is noted in African-American and Hispanic
women. {[}10{]} \textbf{~} There is a need to extend the databases to
include Asian and African populations to identify risk groups in
low-middle-income countries.

Clinically, the majority present with a large, well-circumscribed mass,
usually \textgreater{}5cm. {[}11{]} MpBC tends to have a large tumour
size, rapid growth and less axillary lymph node involvement. {[}6,12{]}~
The present case had a similar large size at presentation keeping with
the literature.

The diagnosis of MpBC is histopathological, thus is highly dependent on
postoperative pathology. There is no typical imaging to discern it from
the other variants of BC, and pathologically, as it is a mixture of two
or more homologous or heterologous components, it can be very difficult
to differentiate it from other rare benign or malignant histologies.
{[}13{]}

Metaplastic carcinomas are on the spectrum of basal carcinomas,
displaying a basal/myoepithelial and epithelial-to-mesenchymal molecular
structure\textbf{.} {[}14{]} \textbf{~} It is a rare heterogenous
subtype characterised by squamous, spindle cell and mesenchymal
phenotype with or without conventional adenocarcinoma component.
{[}15{]}

Histopathological categorization is of cardinal importance as it guides
the prognosis with the squamous variant being the worst. Diagnosis from
cytology is challenging as both epithelial and mesenchymal elements are
essential components. They are known to display positivity for
cytokeratin, S-100 and vimentin or myoepithelial markers like CD10, p63,
and smooth muscle actin. These tumours are mostly sporadic but can arise
from previous lesions like fibroadenoma, spindle cell carcinoma,
papilloma and complex sclerosing lesions. {[}16{]} Beatty et al.
identified 24 MpBC cases which showed high nuclear grade, negative ER/PR
and HER2 status, EGFR positivity and no significant difference in
multidisciplinary treatment patterns, recurrence, or survival, in
comparison to typical BC. {[}17{]} Prior studies have found that MpBC
typically has molecular alterations in epithelial-to-mesenchymal
transition; amplification of epidermal growth factor receptor
(EGFR/HER1); PI3K/AKT, nitric oxide and Wnt/\selectlanguage{greek}β-\selectlanguage{english}catenin signalling;
altered immune response; and cell cycle dysregulation. {[}6{]}

First described in 1987, low-grade adenosquamous carcinoma of the breast
is a rare variant of metaplastic carcinoma. This variant is
characterised by having both squamous and glandular differentiation
embedded in a bland background of spindle cells. {[}18, 19{]} We
describe a similar histological description in our case, and the patient
being cancer-free 3 years on, provides further evidence of the
favourable prognosis due to the low-grade nature of these tumours.

Most MpBC is triple-negative tumours, and thus the management principles
follow those of conventional TNBC. These cancers are treated with
anthracycline, taxane and platinum-based chemotherapy. The larger size
of the tumours, lack of hormone therapy as a systemic treatment, and the
increased risk of metastasis make a case for the increased use of
systemic chemotherapy though the literature bases lack substantial
evidence to support this practice. {[}5, 10{]} Our patient received
NACT, following which the axillary nodes did shrink (negative axillary
dissection specimen), but the tumour however grew in size. The cut
section did however demonstrate a large area of necrosis, which was
pre-empted by the interval sonomammogrphy showing internal echoes.
Variation in response to NACT exists based on the histologic subtype,
with some benefit observed in matrix-producing MpBC. {[}9{]} The role of
NACT in MpBC is still unclear, but may continue to remain the standard
of practice due to the higher risk of metastasis in the absence of it,
and until newer novel therapies are developed.

There have been limited studies regarding the use of adjuvant
radiotherapy, most of which have demonstrated better overall survival
(OS), DFS and reduced recurrence rate. {[}20{]}~ Following the
conventional principles of BC treatment, radiation to the tumour bed is
commonly given with BCS, which has shown some favourable outcomes.
Unfortunately, the published literature has small patient cohorts.
{[}21{]}

Most patients with MpBc receive surgery as a viable treatment option,
especially if presented early with locally advanced operable tumours.
Both mastectomy and breast conservation surgery were performed, with the
former being more commonly performed due to larger tumour size, and high
tumour:normal breast tissue ratio. {[}10, 22{]}

Novel molecular targeted therapies such as poly ADP-ribose polymerase
(PARP) inhibitors, angiogenesis inhibitors (bevacizumab), protein kinase
inhibitors and mammalian target of Rapamycin (mTOR) inhibitors
(temsirolimus or everolimus) have shown good potential for research in
MpBC. The increased expression of EGFR provides an opportunity for
targeted tumour therapy in these tumours. {[}13{]}

Predictors of a poorer outcome are the presence of skin invasion,
younger age at presentation (\textless{}39 years), and appearance of
squamous cell carcinoma in the lymph nodes. {[}11, 16{]}

MpBC represents a heterogeneity in breast malignancies, with a need for
tailoring treatment for the different variants of breast cancer, rather
than approaching it as a single entity. The scarcity of reported cases
of this tumour makes it a therapeutic challenge for oncologists
worldwide. The lack of clear guidelines for management warrants the need
for more research on the entity, with a special focus on targeted
therapy. It also emphasises the need to identify variants of BC and
focus on a tailored approach, rather than a one-size-fits-all approach.

\textbf{Ethical Statement}

Informed consent of the patient was obtained for publishing details of
her disease and treatment

\textbf{Conflict of Interest}

None.

\textbf{Acknowledgments}

The authors have nothing to report.

\textbf{Data Availability Statement}

This is a case report of a single patient, whose details were recorded
and reported. Identification data have not been disclosed to respect the
privacy of the patient.

\textbf{Author Contributions}

All authors had full access to the details of the case and take
responsibility for the accuracy of all information provided.
Conceptualisation \& design - Soirindhri Banerjee. Methodology - Ishika
Mahajan. Investigation - Soirindhri Banerjee and Shivam Chakraborty.
Writing original draft - Soirindhri Banerjee and Shivam Chakraborty.
Review \& Editing - Ishika Mahajan, Aruni Ghose and Stergios Boussios

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