A 41-year-old woman, originally from Peru, with a personal history of overweight (BMI 28 kg/m2), gestational diabetes, impaired fasting glucose (130–150 mg/dl), primary hypothyroidism, dyslipidemia (cholesterol 230–240 mg/dl) and no prior history of alcohol consumption or concomitant medication other than hormone replacement therapy with levothyroxine, presented to her Primary Care Center in September 2020 after detecting a nodule in her left breast during breastfeeding. She had strong family history of breast cancer. Breast ultrasound (US) and magnetic resonance imaging (MRI) showed a 38 mm diameter lump in the left breast, with a mediastinal mass observed on positron emission tomography (PET).
An US-guided core biopsy of the breast showed grade III invasive ductal carcinoma with an immunohistochemistry compatible with a triple negative tumor with high-proliferation rate (Ki 67 70%) and programmed-cell death ligand 1 (PD-L1) positive (SP142 > 1%). A biopsy of the mediastinal mass was also performed, and the pathology report confirmed metastases with similar characteristics to the primary tumor.
Following the diagnosis of mTNBC the patient was enrolled in the ATRACTIB study7 and received first-line therapy with weekly paclitaxel 90 mg/m2 plus atezolizumab 840 mg/m2 every 2 weeks and bevacizumab 10 mg/kg every 2 weeks. During the screening period, abdominal US identified a normal-sized liver with geographic steatosis, with no other focal lesions or evidence of advanced liver disease. Therefore, liver MRI was performed, which confirmed severe steatosis and ruled out metastatic disease. The patient was also evaluated by the Hepatology Department, which excluded additional chronic liver diseases and established the diagnosis of MASLD with a low risk of advanced disease (F3-F4) based on vibration-controlled transient elastography (4 kPa, IQR/med 14%) performed in October 2020, prior to the initiation of systemic therapy. At the time of starting treatment, the patient had grade 1 aspartate aminotransferase (AST) (67 U/L) and alanine aminotransaminase (ALT) (89 U/L) with normal bilirubin but a grade 3 elevation of gamma-glutamyl transferase (GGT) (152 U/L) and a grade 3 of hypertriglyceridemia (537 mg/dL). A low-fat diet was recommended.
The first cycle of the triple regimen was administered in October 2020.
From February 2021, after three cycles of treatment, blood tests demonstrated a progressive increase in AST/ALT levels (up to grade 1), while imaging studies showed a partial response of the disease in metastases and primary tumor, with no evidence of liver metastases.
The patient remained on the same treatment until December 2021. At that time, imaging studies showed a complete radiological response of the mediastinal mass, whereas the primary breast lesion has only partially responded, decreasing to 30 mm. Chemotherapy was subsequently discontinued, while atezolizumab and bevacizumab were maintained until disease progression in the breast in March 2022, when the primary tumor increased to approximately 50 mm. During this period, the patient was also referred to the Endocrinology Department for assessment of glycemic control due to elevated glucose levels, likely related to immunotherapy, and low-dose atorvastatin and metformin were initiated. At that point, second-line therapy with the antibody-drug conjugate praluzatamab ravtansine at a dose of 7 mg/kg was initiated as part of a clinical trial. Despite achieving a partial response, the treatment was discontinued due to grade 2 neurotoxicity and maintenance therapy with oral cyclophosphamide 50 mg per day was started in July 2022. Throughout this period, grade 1–2 elevations in transaminases were observed.
In October 2022, the patient developed disease progression in the breast. Given that the mediastinal disease had remained in complete remission for an extended period, treatment with doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 with a neoadjuvant approach was initiated, aiming to reduce the tumor burden before proceeding with surgery on the primary breast lesion. Baseline transaminases were elevated (AST 157 U/L and ALT 151 U/L), in the absence of other concomitant hepatotoxic medications. A new abdominal CT scan revealed only severe hepatic steatosis. At that time, following evaluation by the Hepatology Department, a new elastography showed worsening compared with baseline (9 kPa, IQR/med 15%). For this reason, a liver biopsy was performed, confirming MASH with NAFLD Activity Score of 7 and grade 2 fibrosis (Fig. 1)8.
Fig. 1: Liver biopsy October 2022.
A Panoramic, B high power. Severe non-alcoholic steatohepatitis. Hepatic parenchyma discloses NAS score 7: steatosis 3 (75%); balloon cells 2 (many of these cells on the right) and inflammatory foci 2 (2–4 accumules in 20x field)
She continued systemic therapy with 4 cycles of doxorubicin plus cyclophosphamide.
In March 2023, prior to surgery on the primary tumor, results from genetic counseling revealed a pathogenic germline variant of BRCA1. However, given the advanced stage of the disease, surgery was performed on the affected breast only. The pathology report confirmed a metaplastic carcinoma, staged as pT3, with a poor response to therapy. Subsequently, the patient received radiotherapy for local disease control. In May 2023, olaparib was initiated at a reduced dose of of 250 mg twice daily, due to the presence of grade 1 transaminase elevation (AST 142 U/L and ALT 129 U/L), two months after completing the last cycle of chemotherapy.
One week after initiating treatment, blood tests showed improvement in liver enzymes (AST 78 U/L, ALT 82 U/L). However, olaparib was discontinued due to the onset of grade 2 fatigue and grade 2 nausea. At that time, a baseline CT scan was performed, revealing a new focal hepatic lesion, with no other signs suggesting tumor recurrence. A subsequent liver biopsy was performed in June 2023, demonstrating patchy steatosis (NAFLD Activity Score of 5 and grade 2 fibrosis), with no evidence of malignant disease (Fig.2).
Fig. 2: Liver biopsy June 2023.
A Panoramic, B high power. Moderate non-alcoholic steatohepatitis. Hepatic parenchyma discloses NAS score 5: steatosis 2 (50%); balloon cells 1 (few cells) and inflammatory foci 2 (2-4 accumules in 20x field)
Three weeks after discontinuing treatment, liver function tests worsened again (AST 162 U/L and ALT 164 U/L). Consequently, olaparib was reinitiated at the same dose (250 mg twice daily), under close monitoring of liver enzymes. Within one week, improvement was observed, with AST 94 U/L and ALT 95 U/L. One month later, the dose was escalated to the standard of 300 mg twice daily. Transaminase levels remained around 90–100 U/L over the following 12 weeks. By November 2023, blood tests showed normalization of liver enzymes, with AST 29 U/L and ALT 31 U/L. No additional hepatic interventions were required, and her weight remained stable throughout the entire period described (75–78 kg), despite recommendations for weight loss; consequently, the observed improvement was considered unlikely to be due to other causes and was instead attributed to the reintroduction of olaparib (Table 1, Figs.3 and 4).
Fig. 3Fig. 4
Transaminases evolution with olaparib.
Table 1 Clinical characteristics, therapies adminitered, and evolution of liver disease before and during olaparib treatment.
At that time, the patient developed mild headache. A brain MRI revealed a new lesion in the cerebellum. Given the absence of extracranial disease and the complete response in the mediastinum, the brain lesion was surgically removed on December 5, 2023. Olaparib had been discontinued 15 days prior to the procedure and subsequently reintroduced. Approximately one month after surgery, the patient experienced worsening neurological symptoms, and imaging studies revealed a recurrence of the tumor at the surgical site. A second surgical intervention was performed; however, her neurological condition continued to deteriorate due to sequelae from the surgical intervention and rapid tumor progression in the surgical bed. Consequently, olaparib was ultimately discontinued in December 2023, and she was referred to a Palliative Care Unit, passing away in March 2024.
