Unilateral lower‐limb vasculopathy: A rare adverse event of CDK4/6 inhibitor in breast cancer

Cyclin-dependent 4/6 kinase inhibitors (CDK4/6i) combined with aromatase inhibitor (AI) is currently recognized as first-line therapy in HR+, human epidermal growth factor receptor 2 (HER2) negative, metastatic breast cancer.1, 2 Cyclin-dependent kinases (CDK) were initially discovered in the cell cycle, while many “cyclins” subunits were recognized as possessing different functions. Unphosphorylated retinoblastoma (Rb) protein plays an important role in restricting cell cycle progression from G1 into S phases, while CDK4 and CDK6 works with cyclin D1 to phosphorylate the Rb protein, and CDK4/6 inhibitors (CDK4/6i) could block this phosphorylation process and maintain the cell cycle progression.3 A 66-year-old female presented to our clinic with huge mass at right breast with skin eruption. She had past history of chronic hepatitis B, hypertension, and type II diabetes mellitus. Computed tomography (CT) revealed right axillary lymph nodes and liver metastasis, with the pathology report confirming ductal carcinoma with estrogen receptor positive (95%), progesterone receptor positive (5%), HER2 negative, and Ki-67 80%, cT4aN3M1. Palbociclib 125 mg was administered daily from Day 1 to Day 21, and letrozole 2.5 mg was given from Day 1 to Day 28 every 4 weeks. The patient tolerated the treatment very well during the initial 4 cycles without obvious adverse events, and the laboratory tests were within normal limits except for Grade 1 neutropenia. CT showed partial response both in breast tumor and liver metastasis, while Ki-67 decreased from 80% to 32%. During the fifth course of treatment, some reddish papules and pustules were initially noted at the lower part of the left lower leg and soon progressed to the entire circumference of the left lower leg (Figure 1A). Easily ruptured blisters then appeared and caused skin erosion with continuous serous discharge (Figure 1B); however, this condition only occurred in the left lower leg while other skin areas were intact, and patient denied recent trauma history or taking Chinese herbal medicine. Laboratory test revealed WBC = 2230/μl, hemoglobin = 9.6 g/dl, platelet count = 9500/μl. A dermatologist was consulted, and leukocytoclastic vasculitis or fixed drug eruption were the possible differential diagnoses. Palbociclib was suspended and the wound gradually healed with xerosis and fissure after 4 weeks of rest (Figure 1C). The adverse events of CDK4/6 inhibitor are usually hematological in character, such as neutropenia, leukopenia, and anemia. Some nonhematological side effects have also been reported such as fatigue (33%–44%), nausea (29%–37%), headache (21%–28%), diarrhea (16%–22%), and alopecia (14%–33%).1, 2 In a Phase III Paloma II trial, 17.8% patients had the adverse event of rash, but only 0.9% patients were Grade 3 or worse; however, footnotes described the rash was not specific and might have included dermatitis, dermatitis acneiform, rash erythematous and toxic skin eruption.4 Cutaneous adverse effects in chemotherapeutic or targeted agents might be seen as papulopustular eruption when taking EGFR inhibitors (gefitinib, erlotinib, cetuximab). This rash would usually appear 1 week after initiating therapy and is correlated with the therapeutic efficacy.5 Herein, we report a rare case of severe unilateral lower-limb vasculopathy after palbociclib and letrozole use, and to our best knowledge, from a PubMed database search, this is the first report. The authors declare no conflict of interests.