Vitiliginous lesions with cyclin-dependent kinase 4/6 inhibitor in a patient with recurrence of breast cancer: A case report and review of the literature

INTRODUCTION

Ribociclib is an inhibitor of cyclin-dependent kinases 4/6 (CDK 4/6) that is used in combination with an aromatase inhibitor as the first-line therapy for advanced or metastatic hormone receptor-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer.^[1] These novel targeted therapeutic agents inhibit cyclin-D/CDK4/6 complex activity and result in hyperphosphorylation of the retinoblastoma protein. This remains bound to the early region 2 binding factor transcription factor and blocks cell cycle progression from the G1 to the S phase.^[2] The most common side effects of CDK 4/6 inhibitors (ribociclib, palbociclib, and abemaciclib) are hematological toxicity, gastrointestinal side effects, and fatigue. Vitiligo-like lesions are a rare side effect of these drugs.^[3,4] Letrozole, an aromatase inhibitor, has been used without reported association with vitiligo,^[5] although subacute cutaneous lupus erythematosus, rheumatoid arthritis, and altered markers of innate, adaptive, and natural killer-cell-related immunity are described following aromatase inhibitors.^[6,7] The modulating effect of letrozole in our case cannot be excluded (Ribociclib’s immune-mediated effects may be exacerbated by letrozole-induced hormonal changes), but a primary role is unlikely. The temporal relationship between depigmentation and ribociclib exposure, and clinical examination, in our case, suggests ribociclib as the cause of vitiligo-like lesions.

CASE REPORT

A 70-year-old female presented with hypopigmented lesions over the face and upper back for 3 months [Figures 1 and 2]. She was diagnosed with locally advanced hormone receptor-positive (Estrogen receptor [ER] 30% and progesterone receptor [PR] 35%)/HER2 (−) breast carcinoma (left side) 15 years ago, following which she underwent left modified radical mastectomy. She was followed up with hormonal therapy after adjuvant chemotherapy and radiotherapy. Three years ago, the patient developed left chest wall recurrence (ER 100%, PR 80%, and HER2 Neu negative), following which she was started on ribociclib (600 mg daily for 3 weeks and 1 week off) and letrozole (2.5 mg daily). Concomitant medications included denosumab, calcium, and an antioxidant. After six cycles of ribociclib, vitiligo-like lesions developed after 3 months on the face and upper back. She was treated with 0.1% tacrolimus with minimal repigmentation.

Close

Figure 1:

Multiple hypopigmented to depigmented lesions over the face (forehead, cheeks, and lips).

Export to PPT

Close

Figure 2:

Hypopigmented to depigmented lesions over the back.

Export to PPT

The patient had no previous history of vitiligo. There was no history of any preceding dermatosis or topical drug application before the onset of lesions. The patient did not have any personal or family history of autoimmunity. The thyroid function test was within normal range. On cutaneous examination, there were well-defined to ill-defined hypopigmented to depigmented macules and patches on the face and upper back.

Further, a woods lamp examination was done that showed bright white, sharply delineated lesions (milky white accentuation) [Figure 3]. Dermoscopy of the lesions showed white structureless areas (black star) with scalloped margins showing absence of pigment network (yellow star), and leukotrichia (black arrow) [Figure 4]. She was not started on any other medication apart from ribociclib recently and had no other comorbidities. The final diagnosis of vitiligo-like depigmenting rash following ribociclib was made based on the evidence of temporal association and relevant clinical examination.

Close

Figure 3:

Woods lamp examination showing bright white, sharply delineated lesions (Milky white accentuation).

Export to PPT

Close

Figure 4:

Dermoscopy of the lesions showing white structureless areas (black star) with scalloped margins showing absence of pigment network (yellow star), and leukotrichia (black arrow).

Export to PPT

DISCUSSION

Vitiligo is an acquired autoimmune disorder characterized by multiple depigmented macules and patches. Vitiligo has been reported as a common immune-related adverse effect in patients with melanoma, non-small cell lung, and kidney cancer treated with anti-programmed cell death protein 1 (PD1)/programmed death-ligand 1 drugs and with tyrosine-kinase inhibitors such as imatinib, cabozatinib, and pazopanib. In the present study, we observed vitiligo-like lesions in a patient with breast cancer on treatment with CDK4/6 inhibitors.

CDK4/6 inhibitors are associated with cutaneous adverse effects, such as alopecia, rash, and pruritus, which usually occur within 1–4 months of treatment initiation. Other side effects include trichorrhexis, onychoclysis, erythema multiforme, bullous dermatitis, and vitiligo.^[8] Ribociclib-induced vitiligo-like lesions involving the photo-exposed areas, trunk, and extremities have been reported more commonly in the 4^th–7^th decade (common age-group for breast cancer). The interval between the development of vitiligo lesions and ribociclib initiation varies between 3 and 10 months.

The exact cause of these lesions is not known. Various hypotheses include:

1. CDK 4 inhibition results in increased senescence of melanocytes.

2. CDK 4/6 inhibitors promote the cytotoxic activity of effector T-cells activity through nuclear factor of activated T cells upregulation and also by inhibition of regulatory T-cells.

3. CDK inhibition in keratinocytes, causing small ubiquitin-like modifier dysregulation, causes melanocyte destruction due to loss of survival stimuli from keratinocytes.

4. CDK 4/6 inhibition may increase the levels of reactive oxygen species in cells through suppression of forkhead box protein M1 phosphorylation, leading to increased apoptosis in melanocytes. However, this phenomenon has not been described in normal melanocytes.^[9]

5. The role of ultraviolet radiation (UVB) is due to the characteristic distribution of the lesions. UVB radiation induces DNA damage, which may be more pronounced in the background of CDK 4/6 inhibition.^[10]

The characteristics of CDK 4/6 inhibitor-induced vitiligo-like lesions in the literature are summarized in Table 1.

There are no treatment guidelines; however, topical steroids, calcineurin inhibitors, emollients, and antihistamines have been used. In extensive cases, oral steroids and phototherapy may be used. The treatment of these cases is challenging, and the aim should be to halt the disease progression rather than repigmentation.^[8,11-14] The depigmentation may lessen over several months after stopping the drug.^[7]

The appearance of vitiligo represents a favorable predicting factor in patients treated with anti-PD1; however, the prognostic value of vitiligo-like lesions in patients treated with CDK4/6 inhibitors is still unknown, and large-scale studies are needed to evaluate this adverse effect.^[13] Considering the increasing use of this medication and the social stigma associated with vitiligo, it is crucial to be aware of this adverse effect and counsel the patients before starting the therapy.

CONCLUSION

CDK 4/6 inhibitors can inhibit cell division and cause premature cell death by acting on the melanocyte cell cycle. The awareness of this side effect is important since these drugs are used increasingly. Vitiligo-like lesions are not a life-threatening side effect. However, it significantly affects the quality of life and disrupts the patient’s compliance with treatment. Early detection, surveillance, and treatment are important to improve the quality of life of these patients.