The patient is a 62-year-old postmenopausal woman diagnosed with a clinical stage 2B hormone receptor positive, HER2-negative left breast cancer. Primary tumor was 3 cm with a 2.5-cm mobile left axillary lymph node. She was otherwise healthy with no significant past medical history. Reported medications included vitamin D-3, citalopram, and zolpidem, and the patient denied use of over-the-counter medications, including herbs and supplements. On average, she reported consumption of seven glasses of wine/week. Her BMI was 30. Baseline liver function tests (LFTs) were in the normal range. Staging PET/CT showed no evidence of distant metastasis.
The patient provided written informed consent prior to screening and again prior to enrollment in the I-SPY 2 TRIAL, a trial testing agents in combination chemotherapy in the neoadjuvant setting in patients with early breast cancer. The trial was approved by the UCSF Institutional Review Board, and written informed consent was obtained for publication of this case report. The goal of neoadjuvant chemotherapy in the treatment of early-stage breast cancer is to down-stage tumors, improve surgical options, and to assess response to therapy which provides valuable prognostic information. Patients in this multi-arm trial are randomized to receive standard chemotherapy or standard chemotherapy in combination with one of several experimental agents. The patient was randomized to an investigational treatment arm including weekly intravenous paclitaxel (80 mg/m2) in combination with oral pexidartinib 1200 mg daily for 12 weeks. The dose of pexidartinib was selected based on safety and efficacy data from a previously reported phase 1b trial of pexidartinib and weekly paclitaxel in patients with advanced solid tumors.
Approximately 3 weeks after starting study therapy (3 doses of weekly paclitaxel and 27 oral daily doses of pexidartinib), the patient was admitted for fever up to 103  F. Initial laboratory studies were notable only for mildly elevated transaminases (ALT 65 U/L, AST 105 U/L) with normal white blood cell count, alkaline phosphatase (ALP), and total bilirubin (Tbili). The patient discontinued all study therapy immediately.
Infectious workup, including blood and urine cultures, viral panel, and chest X-ray were unremarkable. The patient remained febrile to 103.5  F. LFTs continued to rise during the hospitalization, with day 3 studies showing ALT 158 U/L, AST 188 U/L, ALP 119 U/L, and Tbili 1.9 mg/dL (direct bilirubin 1.3 mg/dL). On hospital day (HD) 3, an abdominal ultrasound showed evidence of gallbladder wall thickening and trace peri-cholecystic fluid, but no evidence of cholelithiasis or biliary ductal dilatation. Abdominal/pelvis CT scan showed new diffuse heterogeneous enhancement of the liver with periportal edema and marked gallbladder wall thickening.
Following the abdominal/pelvis CT scan, the patient was started on broad spectrum antibiotics for empiric treatment of acalculous cholecystitis. Hepatobiliary (HIDA) scan showed no focal perfusion defects and was consistent with cholestasis and a high functional obstruction of the common and cystic duct. Magnetic resonance cholangiopancreatography (MRCP) revealed heterogeneous enhancement of the liver without focal liver lesions. There was no intra- or extrahepatic bile duct dilatation and no contrast excretion into the biliary system.
The patient underwent laparoscopic cholecystectomy on HD 6. An intraoperative cholangiogram was performed and did not show significant filling defects, extravasation, or dilatation of the visualized intra- and extrahepatic ducts. The final surgical pathology was consistent with acute cholecystitis.
The LFTs continued to increase post cholecystectomy, with a rise in bilirubin out of proportion to the rise in transaminases. On HD10, ALT was 194 U/L, AST 250 U/L, ALP 377 U/L, and Tbili 10.9 mg/dL. Due to the continued steady rise in bilirubin, a diagnostic endoscopic retrograde cholangiopancreatography (ERCP) was performed on HD10, which revealed a cannulated common bile duct and normal appearing bile duct on cholangiogram. The intrahepatic biliary tree was filled and appeared normal.
A liver core biopsy was performed on HD 11. The biopsy revealed mild cholestasis with small and attenuated bile ducts and focal duct loss. Representative images are shown in Fig. 1, along with a normal liver biopsy for comparison. The portal tracts contained minimal lymphocytic inflammation and no ductular reaction. The lobules showed grade 3 small droplet steatosis without ballooned hepatocytes or Mallory hyaline, and no significant hepatocyte necrosis. In particular, there was no evidence of malignancy. Trichrome stain showed no increased fibrosis. Copper stain was negative, and iron showed 1 + staining in hepatocytes. Overall the findings were of cholestasis with duct damage, and duct loss (only three of eight portal tracts containing ducts) (Fig. 1a). Based on these findings and the patient's clinical presentation, a diagnosis of acute drug-induced liver injury, suggestive of vanishing bile duct syndrome (VBDS) was made, most likely secondary to the experimental agent pexidartinib in combination with paclitaxel.
The patient was started on ursodiol 1200 mg/day for progressive pruritis on HD 12. Prednisone 40 mg daily was started on HD 14, and she was discharged to home on HD 15.
Following discharge, the patient was tapered off prednisone over the course of 1 month. She was started on the aromatase inhibitor, letrozole, 2 weeks after discharge from the hospital. Despite initial improvement in transaminases and ALP, her Tbili continued to rise and remained persistently elevated to a peak of 32.6, 5 months after discontinuation of pexidartinib. Six months after starting letrozole, she underwent left mastectomy and axillary lymph node dissection. Pathology revealed residual 2 -cm grade 2 invasive ductal carcinoma with a cellularity of 5%. Notably, 20 axillary nodes were negative for carcinoma demonstrating an excellent response to neoadjuvant systemic therapy.
Over the following 13 months, the patient's LFTs remained abnormal with ALT/AST 150-200 U/L, ALP 350-400 U/L, and Tbili 20-25 mg/dL. During this time, her functional status deteriorated due to progressive fatigue, anorexia, pruritis, and depression. Greater than 50% of her time was spent in bed, and she lost 60 pounds. She remained on ursodiol and doxepin for pruritis, as well as monthly vitamin K injections. Due to chronicity and severity of her symptoms, the patient underwent orthotopic liver transplant 20 months after her initial diagnosis of severe DILI.
The liver explant showed cirrhosis with cholestasis, loss of interlobular bile ducts, and extensive ductular reaction. Larger bile ducts appeared intact without duct damage. No significant steatosis was seen (grade 0). Overall, the findings were consistent with ductopenia, likely secondary to drug-induced vanishing bile duct syndrome (Fig. 1b, c).
Following transplantation, the patient's LFTs and performance status improved precipitously. She is currently on chronic immunosuppression with everolimus and is thriving clinically 22 months post transplant. Her appetite and energy have significantly improved, pruritis has resolved, and she is at a healthy weight. She remains disease free from breast cancer on adjuvant letrozole. The trend in her LFTs pre- and post transplant are outlined in Fig. 2.