Breast cancer remains the most common and second most lethal cancer among women in the United States [1]. Approximately 50% of patients with breast cancer will develop liver metastases [2]. In some of these patients, metastatic lesions to the liver are the only sign of tumor dissemination, and several studies have shown an association between surgery and long-term survival if a complete resection of the disease is pursued. However, only 20%−30% of patients with stage IV disease at diagnosis are amenable to surgical resection [3]. Patients diagnosed with unresectable breast cancer liver metastasis (BCLM) face a dismal prognosis, with a median survival of up to 12 months [4]. However, the improvements in systemic treatments and the use of monoclonal antibody therapy shown good results, increasing both survival and disease control [5,6]. Furthermore, locoregional therapies, such as transarterial chemoembolization and transarterial radioembolization (TARE), have been demonstrated to be effective strategies to control and sometimes downstage, primary and metastatic liver tumors, even unresectable BCLM [7-9].

Liver transplantation (LT) is considered the treatment of choice in the case of end-stage liver disease and/or primary liver tumors within predefined criteria. Furthermore, there has recently been an increasing interest in transplantation for non-primitive liver cancer in selected cases of metastatic tumors (i.e., neuroendocrine, colorectal, and gastrointestinal stromal tumors) [10-12]. Despite these encouraging results, BCLMs are still considered an absolute contraindication to LT, due to the poor prognosis, and the lack of evidence to justify the use of organ transplants with such an aggressive disease. In this manuscript, we describe the case of a 41-year-old female diagnosed with unresectable BCLM undergoing LT for liver failure following multiple systemic and locoregional treatments. We sought to investigate the long-term oncological results, and discuss whether this approach should be further pursued, or not.

The study was approved by the local Institutional Review Board and by the Italian National Transplant Center (no. 2019/02). Written informed consent was obtained from all participants.

A 41-year-old female was diagnosed with breast cancer, for which she underwent a quadrantectomy and axillary lymphadenectomy in January 2000. Pathological examination revealed a multifocal intra and extra-ductal breast cancer (staging pT1N0, 0/18 lymph nodes, G3) with estrogen receptor (ER) positivity (70%), and progesterone receptor (PR) positivity (65%), human epidermal growth factor receptor 2 (HER2) positivity 3+, and Ki67 15%. The patient then underwent 6 months of adjuvant chemotherapy with cyclophosphamide, methotrexate, and 5-fluorouracil and radiation to the axilla, followed by Tamoxifene till July 2006. The patient was then enrolled in a standard follow-up including clinical encounter, imaging, and laboratory analysis. In June 2008, the patient presented with sudden jaundice and a computed tomography (CT) scan showing multiple liver lesions (Fig. 1). No extrahepatic disease was present at that time. A liver biopsy confirmed metastasis from breast cancer. Tumor markers were elevated, with a CEA of 1,030 IU/mL and a CA 15.3 of 596 IU/mL. Chemotherapy was initiated using paclitaxel and trastuzumab between July 2008 and February 2009, with good response (80% volume reduction) according to the mRECIST criteria [13], and CEA and CA 15.3 reduced within the normal range. In May 2009, the patient underwent TARE with Yttrium-90 with a dose of 220 Gy. Following TARE, Fulvestrant and trastuzumab systemic treatment was maintained. Unfortunately, the progression of the disease was later diagnosed on imaging: a liver biopsy proved a high expression of HER2 and Ki67 (80%). A second line of chemotherapy with Paclitaxel and Trastuzumab was therefore started. This therapeutic scheme was further modified by switching to Fulvestrant and Trastuzumab, and continued until 2016, when a CT scan showed a complete regression of the liver lesions. Nine months later, a single 2 cm metastasis was detected, and confirmed at liver biopsy (ER and HER2 positive). The multidisciplinary decision was to treat this lesion with radiofrequency ablation (RFA), which she underwent in December 2017. She then followed maintenance treatment with Fulvestrant and Trastuzumab for eleven months. A second RFA on the same nodule was performed 6 months later, together with a hyper-selective TARE using 210 Gy. In July 2018, a positron emission tomography with fluorodeoxyglucose (PET-18FDG) showed the persistence of a vital hepatic metastasis (standardized uptake value 6.8), for which the patient underwent a third RFA. After one week, she developed liver decompensation with jaundice, ascites, and portal hypertension; the model for end-stage liver disease (MELD) score was 25. CT, magnetic resonance imaging (MRI) with a liver-specific contrast agent, and PET-18FDG showed minimal persistence of disease at the site of previous loco-regional treatments. Despite specific medical therapy, liver function did not improve, and the MELD score reached 27. The patient was not eligible for further local or systemic treatments to control her disease, and was finally referred to our unit to discuss the option of an LT for her rapidly progressing liver failure. Her clinical and oncological history was discussed during a multidisciplinary meeting. An extensive diagnostic work-up to exclude extrahepatic disease was performed. In addition to the standard pre-LT evaluation including CT, MRI, and PET-18FDG, a liquid biopsy for detecting circulating tumor cells and a diagnostic laparoscopy with cytological examination to exclude peritoneal carcinomatosis were performed; none of the above-mentioned showed evidence of extrahepatic disease, and tumor markers remained within the normal range. Despite further intensive medical therapy, the general and liver-related conditions of the patient further worsened. The local ethical committee and the Italian national committee for organ sharing accepted the patient’s listing for LT under an experimental protocol. A deceased donor orthotopic LT was successfully performed in July 2019 with an extended criteria graft. During surgery, 2 L of ascites were aspirated, and numerous portosystemic shunts were present. An extremely dysmorphic liver, with almost complete atrophy of the left lobe and of the caudate process, with intense scarring from TARE, was noted. The hepatic pedicle was extremely inflamed, and the hepatic vein confluence was scarred and retracted. Liver mobilization was technically difficult, given the adhesions between the liver and the diaphragm following the multiple RFA and TAREs. The operative time was 6 hours 13 minutes. Blood loss was 1 L with 2 units of blood and 6 of plasma transfused. A T-tube was left in place to protect the biliary anastomosis. Cold ischemia time was 5 hours 45 minutes. The postoperative course was uneventful, and the patient was discharged home 10 days after surgery. The patient was followed up weekly for the first month, and every 2 weeks for the following 2 months, and no postoperative complications or readmissions occurred. Pathological examination of the explanted liver showed one single nodule of 3 cm with partial necrosis, and no signs of vascular invasion. Hepatic perihilar lymph nodes were negative. Fig. 2 shows the explanted liver and the effects of previous treatments, which were mainly attributable to actinic hepatitis by radioembolization, with massive liver fibrosis. Immunosuppression therapy consisted of basiliximab, and then calcineurin inhibitors and mycophenolate mofetil in the early postoperative period, therefore suggesting a steroid-free approach. mTOR inhibitor was added after 2 months. A 12-month cycle of adjuvant treatment with trastuzumab was started following LT as part of the protocol. Fifteen months after LT, and 3 after trastuzumab interruption, a CT scan showed a multifocal relapse in the liver (Fig. 3). A liver biopsy was performed, which showed metastases from invasive ductal carcinoma, ER−, PR−, HER2 3+, Ki67 40%. From July to September 2020, the patient was started on chemotherapy with Pertuzumab, Trastuzumab, and Docetaxel. No adverse effects of chemotherapy were reported by the patient. At restaging, radiological complete regression of the liver lesions was shown. In October 2021, the patient developed 2 brain lesions in the right frontal area and the right precentral gyrus, which were treated with radiosurgery (6 X-FFF, True Beam STx, Varian Medical Systems, Inc.) with 20 Gy in a single administration. A modulated radiation was used (RapidArc, Varian Medical Systems, Inc.), which was verified with cone beam CT and ExacTrac Dynamic (Brainlab). No adverse effects of the above-mentioned treatment were reported. Currently, the patient is in good clinical condition, continuing her therapy with trastuzumab and pertuzumab, and a recent CT performed in January 2024 showed no disease in the liver (Fig. 4).

Fig 1. Presentation of the metastatic disease of the liver in 2008.

Fig 2. Explanted liver after transplantation.

Fig 3. Magnetic resonance imaging showing multifocal recurrence in the transplanted liver.

Fig 4. Computed tomograpy scan at last follow-up (January 2024), 54 months after transplantation, showing complete response after systemic treatment.

LT for tumors other than hepatocellular carcinoma represents a clinical challenge that has been increasingly investigated, such that there is a growing interest in what is nowadays called “transplant oncology”. This enthusiasm was initially triggered by the interesting results shown by the SECA I and SECA II randomized controlled trials investigating the role of LT in unresectable colorectal cancer metastasis [14,15]. These studies have indeed reported promising survival rates of 80% at 4 years for patients who were otherwise candidates for palliative therapy, and therefore bearing a dismal prognosis. Furthermore, despite the recurrence rates in these studies being rather high (60% at 2 years from transplant) and mainly in the lungs, the overall survival of patients was still long, as the disease was well controlled by systemic treatment. The application of more stringent inclusion criteria in the second of these trials (SECA II) further reduced the occurrence of relapse: this was due to the need for 12-month stability of disease diagnosed with PET/CT to exclude aggressive disease, and a biological evaluation of the disease using oncological biomarkers. The results of the above-mentioned trials led to the application of LT as a therapeutic option for patients with unresectable colorectal liver metastasis in many countries worldwide. Unfortunately, as this option is still considered “experimental”, the numbers are not high enough given the scarcity of organs, which is a worldwide limitation of the solid organ transplantation network. In this setting, further metastatic diseases are considered absolute contraindications to LT, because of the poor results achieved in preliminary experiences. Unresectable breast cancer liver metastases are currently considered manifestations of end-stage disease having dismal prognosis, and are referred to palliative systemic treatment [16]; neither surgical options nor LT are considered in this case. This is mainly due to the disappointing results published in the early 90s [17]. Here, LT was undertaken in a few patients who failed chemotherapy and surgery, and were diagnosed with disease progression. Furthermore, no post-transplant adjuvant chemotherapy was performed. In other experiences, the diagnosis of breast cancer metastasis was performed on the explanted liver, as the lesions were erroneously interpreted as primary liver cancer before LT. Here, the relapses were very early, and the progression of the disease was rapid, with a very short post-transplant survival rate. The dismal results achieved in this setting are therefore a consequence of poor selection, inadequate management of patients and disease, and wrong utilization of organ resources. In an interesting case reported in 2003, Wilson et al. [6] presented the outcomes of a 25-year-old female undergoing LT for what was supposed to be an intrahepatic cholangiocarcinoma, but turned out to be a metastatic breast cancer on explant pathology. Interestingly, despite the patient recurring 2 months after transplantation, she was still alive after 33 months thanks to systemic therapy. In the case we herein report, the disease was preoperatively well controlled, with no signs of activity, low tumor markers, and a long interval of the disease’s stability. These features allowed us to consider the option of LT, because the biological information that we had available was consistent with disease stability. Furthermore, the use of diagnostic laparoscopy and circulating tumor cell identification further allowed us to exclude any signs of undetected disease.

The progress achieved in the systemic treatment of breast cancer has dramatically changed the natural history of the disease. Specifically, hormone receptor treatment allowed prolonged survival and reduced relapses. The patient we are herein reporting had hormone receptor expression and overexpression of HER2 in cancer cells as a further selection criterion, so that she could have a targeted treatment, both as neoadjuvant and adjuvant strategies, to control the disease and reduce and treat recurrences. Despite applying the above-mentioned strict selection criteria, our patient recurred in the liver 15 months after LT. This happened as soon as the patient interrupted systemic treatment. Furthermore, soon after the diagnosis of recurrence, chemotherapy was started again, and the disease was well controlled, affecting neither overall survival, nor quality of life. Trastuzumab allowed for disease control both after LT and after diagnosis of recurrence, supporting its use in receptor-positive BCLM [18]. As further information, the immunosuppressive regimen after transplantation was designed to minimize the suppressive effect on oncological surveillance, avoiding steroids and starting the immunosuppressive regimen with mTOR inhibitors soon after LT.

It must be mentioned that the reason for our patient receiving transplantation was liver failure, and not the oncological disease itself. Indeed, BCLMs were the “comorbidity”, rather than the etiology, in this case of LT. The conclusions we are therefore drawing are speculations on the case that, in our opinion, are interesting in the understanding of the history of breast cancer and the therapeutic options. It is therefore very cautiously understood in our preliminary report that LT is not an alternative to surgery or chemo/locoregional therapy. Indeed, we performed this case after the approval of a specific protocol that was submitted to the local ethical committee of our hospital and the Italian National Transplant Center. According to the national authorities, every year 5% of the Italian organ resources can be allocated to experimental indications, after the approval of a specific protocol. Our patient was transplanted within this policy.

In conclusion, we share our case of LT following iatrogenic liver failure in a patient with metastases from breast cancer. LT for this highly selected patient with BCLM showed a good clinical outcome. Perioperative systemic treatment and tumor control are necessary. A specific protocol should be discussed within a multidisciplinary team, and with local and national authorities. Even if the tumor recurs, multimodal therapies can control the disease. Despite our recognizing that LT should be performed in other metastatic liver tumors only following solid literature sustaining oncological adequacy, experimental conditions should be investigated, provided a strict selection of candidates is made.

None.

No potential conflict of interest relevant to this article was reported.

Conceptualization: GME, GB, VG. Data curation: GME, GB, VG, MC. Methodology: GME, GB, VG, MC. Visualization: GB, LDC. Writing - original draft: GME, GB, VG, RC, AP, GV, EC. Writing - review & editing: RM, NG, SF, LDC.