Elevated liver function tests in a patient on palbociclib and fulvestrant

Labs checked on April 28 and May 26 were unremarkable. A restaging CT scan of the chest, abdomen, and pelvis was done on June 21 after completion of 3 cycles of fulvestrant and palbociclib. There was no evidence of liver metastases, only the fatty infiltration of the liver that had been seen previously. On June 23, 2017, lab results showed a transaminitis with an alanine aminotransferase (ALT) level of 446 IU/L (reference range 10-33 IU/L) and aspartate aminotransferase (AST) level of 183 IU/L (reference range 0-32 IU/L).

The patient’s liver enzyme levels continued to increase and peaked on July 3 at ALT >700 IU/L and AST at 421 IU/L. Her total bilirubin and alkaline phosphatase levels remained within normal limits. She had received her final dose of fulvestrant on May 31 and had taken her last dose of palbociclib on June 20, 2017. She had no history of elevated liver enzymes or liver disease, although the initial PET scan done at diagnosis had suggested hepatic steatosis. She said she had not recently used antibiotics, alcohol, or over-the-counter medications or supplements. There was no family history of liver problems, inflammatory bowel disease, or gastrointestinal malignancy. The only other medications she had taken recently were denosumab, levothyroxine for hypothyroidism, and amlodipine for hypertension. She was seen by hepatology for evaluation of acute hepatitis. Other etiologies for her elevated liver enzymes were ruled out, and she was diagnosed with a drug-induced liver injury from one of her anticancer medications. Her treatments with fulvestrant and palbociclib were held, and the results of her liver function tests normalized by September 2017.

Fulvestrant was restarted on August 24, and her lab results remained normal through November of that year, when restaging scans showed progression with new axillary adenopathy suspicious for metastasis. Imaging also showed a 1.6-cm hepatic lesion suggestive of a focal area of fat deposition or atypical hemangioma without definitive evidence of metastasis. Follow-up imaging was recommended. She was therefore rechallenged with palbociclib at a reduced dose of 100 mg by mouth daily and received the first dose on November 30. On December 8, repeat labs again showed elevated liver function tests (ALT, 285 IU/L; AST, 112 IU/L). Treatment with palbociclib was discontinued on December 10. Because the patient was not able to tolerate palbociclib, and fulvestrant alone was not controlling the disease, she was started on an alternate endocrine therapy with tamoxifen on December 26. The patient’s liver function tests normalized again by January 2018.
 

Discussion

The use of targeted therapies has changed the landscape of oncologic treatments. Several studies have evaluated the safety and efficacy of palbociclib in combination with endocrine therapy. The Palbociclib Ongoing Trials in the Management of Breast Cancer (PALOMA)-1 study, an open-label, randomized, phase-2 trial involving patients with newly diagnosed metastatic hormone sensitive HER2-negative breast cancer, demonstrated that palbociclib in combination with letrozole was associated with significantly longer PFS than letrozole alone.⁴ These results were later confirmed in the larger PALOMA-2 study, a randomized, double-blind, phase-3 trial that evaluated 666 postmenopausal patients with no prior systemic therapy. In that study, median PFS for the palbociclib–letrozole group was 24.8 months, compared with 14.5 months for the letrozole-alone group (hazard ratio [HR] for disease progression or death, 0.58 [0.46–0.72], P < .001).⁵ The most recent PALOMA-3 study, a phase-3 trial involving 521 patients with advanced hormone receptor–positive, HER2-negative breast cancer that had progressed during initial endocrine therapy, evaluated the efficacy of combined palbociclib and fulvestrant in a randomized, double-blind, placebo-controlled, parallel-group trial. The result was that the palbociclib–fulvestrant combination resulted in longer median PFS of 9.2 months, compared with 3.8 months with fulvestrant alone (P < .001).⁶