Keywords breast cancer - dual anti-HER2 blockade - focal nodular hyperplasia - pertuzumab -
trastuzumab
Introduction
HER2 overexpression is present in approximately 25% of breast cancers, often resulting
in a more aggressive disease compared with breast cancers without HER2 overexpression.
Targeted therapies such as trastuzumab and pertuzumab have greatly enhanced outcomes
for patients with HER2-positive breast cancer.[1 ] These therapies are generally associated with fewer side effects. Hepatic complications
are infrequently reported following the use of these anti-HER2 monoclonal antibodies.[2 ]
[3 ] This case report discusses a patient who developed focal nodular hyperplasia (FNH)
of the liver after receiving trastuzumab and pertuzumab, highlighting the importance
of considering potential hepatic toxicities in those undergoing dual anti-HER2 therapy.
Case Report
A 61-year-old postmenopausal woman with a medical history of hypertension, diabetes
mellitus, and hypothyroidism presented with a left breast lump in May 2018. A core
biopsy confirmed the diagnosis of breast cancer, immunohistochemistry showing positive
estrogen receptor (ER), positive progesterone receptor (PR), and HER2 neu overexpression
(3 + ). She underwent a left modified radical mastectomy. Owing to the strong hormone
receptor positivity and localized stage II disease, chemotherapy with targeted therapy
was advised. However, the patient declined and was subsequently initiated on adjuvant
anastrozole, an aromatase inhibitor.
The patient initially tolerated the adjuvant treatment well. However, 6 months into
therapy, she began to experience bone pains and serous discharge from the anterior
hip region. A positron emission tomography and computed tomography (PET-CT) scan in
June 2019 showed no residual breast disease, but revealed mediastinal and abdominal
lymphadenopathy with low-grade metabolic activity, along with an osteolytic lesion
at the left anterior superior iliac spine with sinus tract formation. These findings
indicated the presence of metastatic disease. The patient's treatment was transitioned
to ribociclib, a CDK4/6 inhibitor, in combination with fulvestrant. Despite this change,
a follow-up PET scan 3 months later showed no substantial reduction in the disease.
With this history, the patient approached us for the next line of therapy. Consequently,
the treatment regimen was changed to systemic chemotherapy with weekly Nab-paclitaxel
(100 mg/m2 ) and trastuzumab (4 mg/kg followed by 2 mg/kg), along with bone-modifying agent denosumab
every 3 months. The patient tolerated 18 cycles of weekly chemotherapy achieving a
remarkable response. Subsequent evaluations, including comprehensive liver function
tests (LFTs) and an abdominal scan, demonstrated no evidence of liver disease. As
a result, she was placed on maintenance therapy with trastuzumab and pertuzumab alongside
fulvestrant starting from March 2020. The interim evaluations and PET scan in January
2024 confirmed the absence of active disease or any recurrence during this period,
leading to the continuation of trastuzumab and pertuzumab with fulvestrant to date.
In July 2024, a follow-up PET-CT scan revealed an ill-defined hypodense lesion with
clustered hypodensities in the splenic parenchyma, demonstrating increased metabolic
activity (SUVmax of 8.7; [Fig. 1 ]), suggestive of a granulomatous pathology. Subsequent magnetic resonance imaging
(MRI) of the abdomen showed an enhancing, geographic, non-mass-like lesion with indistinct
margins in the spleen, which was not clearly visible on structural imaging, indicating
a likely inflammatory or immune response rather than metastatic disease. Additionally,
the MRI identified numerous (>20 lesions) arterial-enhancing nodular lesions (3–10 mm)
with restricted diffusivity scattered throughout both liver lobes, which were not
metabolically active ([Fig. 2 ]). These findings were consistent with asymptomatic FNH or nodular regenerative hyperplasia.
At the time of hepatic nodule diagnosis, the patient's LFTs and tumor markers including
alpha-fetoprotein (AFP) were within normal ranges, and viral hepatitis serology was
negative. She also had no history of smoking, alcohol use, hepatotoxic medication
use, or any relevant family history. Due to the patient's refusal of a liver biopsy,
the absence of washout on MRI and lack of fluorodeoxyglucose (FDG) uptake on imaging
led to the conclusion of FNH induced by trastuzumab and pertuzumab treatment. Hepatology
consultation was taken and they advised the patient to continue trastuzumab + pertuzumab
therapy and to observe the hepatic and splenic lesions over the next 3 to 6 months.
Fig. 1 Focal fluorodeoxyglucose (FDG) uptake adjacent the splenic hilum with mild enhancement
without any signal alteration on T2-weighted/diffusion-weighted (DW) images.
Fig. 2 Multifocal arterial enhancing lesions with diffusion-weighted (DW) hyperintensity
scattered in both lobes of the liver.
Discussion
This case highlights the development of FNH induced by administration of dual targeted
therapy and the absence of history of chronic liver disease, smoking, alcohol, or
medication use strongly suggests a cause–effect association.
FNH is marked by micronodularity (<0.2 cm) and diffuse transformation of the liver
parenchyma without fibrosis, arising from altered intrahepatic blood flow. This causes
reduced portal flow and hepatocyte atrophy, which is compensated by increased blood
flow in adjacent areas, leading to hepatocyte hyperplasia and regenerative nodule
formation.[4 ] Drug-induced FNH is rare and asymptomatic, typically arising after prolonged treatment
and is most commonly associated with thiopurines, antiretrovirals, and platinum-based
drugs.[5 ] Since most drug-induced FNH cases are asymptomatic and are without carcinomatous
change, accurate diagnosis of hepatic nodules during therapy is crucial, as FNH and
liver metastases have markedly different prognosis. MRI is currently considered the
best noninvasive method for diagnosing drug-induced FNH, with a sensitivity of 70%
and specificity of 98%.[6 ] A definitive diagnosis of classical FNH is easily made when MRI shows a homogeneous
tumor with a central scar and arterial-phase hypervascular enhancement. In the present
case, FNH was diagnosed using a combination of imaging techniques, including ultrasonography,
PET-CT, and MRI, which have a reported diagnostic accuracy of up to 90%.[7 ]
Although there are limited data of anti-HER2 therapy causing FNH, cases of trastuzumab
and pertuzumab directly causing liver hyperplasia have been reported. A case has been
reported by Force et al wherein trastuzumab emtansine combined with pertuzumab was
associated with the development of FNH of the liver.[8 ] In a clinical trial, a patient developed acute liver failure after receiving pertuzumab,
trastuzumab, and docetaxel, although the role of pertuzumab in this event is unclear.[3 ] Liver injury linked to trastuzumab is typically self-limiting and not accompanied
by symptoms like jaundice. In contrast, hepatotoxicity associated with ado-trastuzumab
emtansine can often be severe and fatal.[9 ] Fulvestrant can cause liver enzyme elevation in up to 15% of cases, with rare instances
of hepatitis and liver failure, but is not linked to steatosis or fatty liver disease.[10 ] Ribociclib, a CDK4/6 inhibitor, is primarily associated with neutropenia, QTc prolongation,
and diarrhea, although rare cases of hepatotoxicity and pseudocirrhosis have been
reported.
Hepatic changes typically appear after a median of two chemotherapy lines and four
systemic treatments, including endocrine therapy and CDK4/6 inhibitors.[11 ] Trastuzumab inhibits HER2 signaling by binding to its extracellular domain, while
pertuzumab complements this action by blocking HER2 heterodimerization and enhancing
antibody-dependent cytotoxicity; both agents generally cause mild, transient liver
enzyme elevations, with rare severe hepatotoxicity, particularly in combination therapies.[12 ] In present case, the patient was asymptomatic and it was only an accidental finding
and had no liver metastases, unlike most cases of history with liver cirrhosis that
arises on preexisting liver metastases or after multiple lines of systemic therapy.
Typical FNH is diagnosed through imaging without biopsy, and recognizing its imaging
characteristics and related conditions enables accurate diagnosis, avoiding unnecessary
anxiety and biopsy risks.[13 ] In the present case, MR images showing the absence of washout, along with PET scans
indicating no FDG avidity, led to the diagnosis of FNH associated with trastuzumab
and pertuzumab treatment.
To the best of our knowledge, the occurrence of FNH associated with the use of pertuzumab
and trastuzumab is not well documented in the literature. The potential therapeutic
approaches include withholding the treatment and reassessment or a change in therapy
regimen. While FNH is generally considered benign and asymptomatic, its occurrence
following targeted HER2 therapy warrants attention. The pathophysiological mechanisms
linking dual anti-HER2 therapy, specifically trastuzumab and pertuzumab, to the development
of FNH are not yet fully understood, but may involve vascular changes induced by the
treatment. Further research is needed to clarify the relationship between anti-HER2
therapy with pertuzumab and trastuzumab and hepatic changes, and to establish evidence-based
guidelines for monitoring and managing these conditions. Additionally, the absence
of long-term follow-up data restricts the understanding of the potential progression
of FNH in patients undergoing extended anti-HER2 therapy. Larger, prospective studies
will help understand the incidence, risk factors, and clinical implications of FNH
in this patient population.
Conclusion
Our experience suggests that FNH may develop as a rare side effect of dual anti-HER2
therapy with pertuzumab and trastuzumab. Although generally benign, this finding highlights
the need for careful monitoring and further research to elucidate the relationship
between these therapies and hepatic changes.
