Palbociclib is a unique cyclin-dependent kinase inhibitor that is used in combination with aromatase inhibitors in the treatment of postmenopausal women with metastatic breast cancer. Palbociclib is associated with transient and usually mild elevations in serum aminotransferase during therapy and to an unusual form of liver injury called pseudocirrhosis caused by shrinkage of tumor metastases in the liver combined with desmoplastic changes and vascular damage, that can be severe, progressive and even fatal.


Palbociclib (pal" boe sye' klib) is an orally available, specific inhibitor of cyclin-dependent kinases that is used in combination with aromatase inhibitors in the therapy of postmenopausal women with metastatic breast cancer that is positive for the estrogen receptor (ER+), but negative for human epidermal growth factor receptor 2 (HER2-). The cyclin kinases 4 and 6 regulate the cellular transition from the G1 to the S phase of the cell cycle. Inhibition of this transition blocks the progression of the cell cycle and results in growth arrest in rapidly dividing cells. The addition of palbociclib to letrozole or fulvestrant (aromatase inhibitors) therapy of metastatic breast cancer (ER+, HER2-) in postmenopausal women was associated with a prolongation of disease free survival. Palbociclib received accelerated approval for use in the United States in 2015, and it is still under close evaluation for its long term safety and efficacy. Palbociclib is available in capsules of 75, 100 and 125 mg and the typical maintenance dose is 125 mg once daily in 21 day cycles every 28 days indefinitely or until there is disease progression. Common side effects include fatigue, nausea, diarrhea, anorexia, neutropenia, fever, anemia, thrombocytopenia, epistasis, peripheral neuropathy and pulmonary embolism. Severe adverse events include neutropenic fever and sepsis.


In the large clinical trials, adverse events were common and led to dose reductions in one-third of patients and discontinuation in 8%. Publications on the efficacy and safety of palbociclib rarely mentioned serum ALT elevations or hepatotoxicity. In a study of women with refractory, metastatic breast cancer, serum ALT elevations occurred in 6% [2% over 5 times ULN] receiving palbociclib and fulvestrant compared to 3% [none over 5 times ULN] on fulvestrant alone. Since its approval and more widescale use, there have been several reports of prominent ALT elevations arising after 2 or 3 cycles of palbociclib, that improved on discontinuation and recurred rapidly when restarted. Serum bilirubin and alkaline phosphatase levels were normal and symptoms were not mentioned. In addition, there have been rare reports of patients with refractory metastatic breast cancer who developed pseudocirrhosis within 2 to 3 months of starting palbociclib presenting with fatigue, jaundice and ascites with only modest elevations in serum aminotransferase and alkaline phosphatase levels. Imaging revealed a severely nodular liver, but liver histology showed desmoplastic changes in areas of necrotic metastatic tumor without cirrhosis. The liver also had vascular changes suggestive of sinusoidal obstruction syndrome, changes possibly caused by the dramatic involution of the metastatic tumor tissue combined with vascular damage. Pseudocirrhosis has been reported with other highly successful antineoplastic therapies of cancer metastatic to the liver, but the frequency is rare.

Likelihood score: C (probable rare cause of clinically apparent liver injury that may represent pseudocirrhosis from nodular transformation of the liver in response to necrosis of hepatic metastases).

Mechanism of Injury

The possible causes of serum enzyme elevations or liver injury from palbociclib therapy are not known. Palbociclib is metabolized in the liver largely through the CYP 3A4 pathway and liver injury might be caused by production of a toxic or immunogenic intermediate. Because it is a substrate for CYP 3A4, palbociclib is susceptible to drug-drug interactions with agents that inhibit or induce this specific hepatic microsomal activity. Pseudocirrhosis due to palbociclib is thought to be due to the necrosis and involution of hepatic metastases that cause an altered hepatic architecture and vasculature resulting in liver dysfunction.

Outcome and Management

Serum aminotransferase elevations above 5 times the upper limit of normal (if confirmed) or any elevations accompanied by jaundice or symptoms should lead to dose reduction or temporary cessation. There is no evidence to suggest a cross reactivity in risk for adverse events, hypersensitivity or hepatic injury between palbociclib and other cyclin dependent kinase inhibitors.

Drug Class: Antineoplastic Agents, Protein Kinase Inhibitors

Other Cyclin-Dependent Kinase Inhibitor Drugs: Ribociclib



Palbociclib – Ibrance®


Antineoplastic Agents


Product labeling at DailyMed, National Library of Medicine, NIH



References updated: 10 April 2020

Abbreviations: ER, estrogen receptor; HER2, human epidermal growth factor receptor 2.

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    (57 year old woman with metastatic breast cancer developed abnormal liver tests after 3 monthly cycles of palbociclib and fulvestrant [ALT 446 U/L, bilirubin and Alk P normal], which resolved within 4-6 weeks despite restarting fulvestrant but then recurred within 10 days of restarting palbociclib [ALT 285 U/L]).
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