Presentation and management of diverse cutaneous reactions after cyclin-dependent kinase 4/6 inhibitor use

To the Editor: Small-molecule, cyclin-dependent kinase (CDK) 4/6 inhibitors (CDK4/6is), including palbociclib, abemaciclib, and ribociclib, first obtained regulatory approval for hormone receptor+ breast cancer patients who have progressed or relapsed on standard endocrine therapy. CDK4/6is have been shown to increase progression-free survival when used in combination with endocrine therapy following disease progression on endocrine therapy alone.1Turner N.C. Slamon D.J. Ro J. et al.Overall survival with palbociclib and fulvestrant in advanced breast cancer.N Engl J Med. 2018; 379: 1926-1936Crossref PubMed Scopus (502) Google Scholar, 2Finn R.S. Crown J.P. Lang I. et al.The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study.Lancet Oncol. 2015; 16: 25-35Abstract Full Text Full Text PDF PubMed Scopus (1284) Google Scholar, 3Sledge Jr., G.W. Toi M. Neven P. et al.MONARCH 2: abemaciclib in combination with fulvestrant in women with HR+/HER2advanced breast cancer who had progressed while receiving endocrine therapy.J Clin Oncol. 2017; 35: 2875-2884Crossref PubMed Scopus (775) Google Scholar Although CDK 4/6is demonstrate promising efficacy, their unique mechanism of action is also associated with numerous toxicities. Cutaneous side effects have been reported; however, the literature is lacking in specific descriptions. Given the increasing use of CDK 4/6i, further descriptions of adverse cutaneous manifestations are needed, including morphology, time to symptom onset, alleviating factors, and effect on cancer therapeutic course. Inpatient data from 2016-2020 was used to identify 9 patients with hormone receptor+ breast cancer and 1 patient with liposarcoma who had received treatment with CDK 4/6i and experienced the development of cutaneous reactions. The cases were categorized based on patient demographics, time from drug initiation, morphology, distribution, and alleviating factors (Table I).Table IPatient demographics, CDK4/6i agent used, duration to rash development, rash morphology and treatment, and impact on CDK4/6i therapyPatient numberAge, YearsRaceCancer1st CDKiRash Onset1st CDKiCDKi ChangeRash Onset2nd CDKiCDKi ChangeRash DescriptionsMorphologyDistributionEffective Tx146CaucasianGrade 1 ER+, PR+, HER2 IHC 1+ w/ liver metsPalbociclib21 daysHeld, then continued after rash txN/AMorbilliform w/mucosal erosionsExtremitiesTrunkPalmsTriamcinolone cream 0.1%, Magic mouthwash238CaucasianGrade 3 ER+, PR+, HER2− w/ node and bone metsPalbociclib11 monthsDiscontinuedN/APapulopustular rosaceaFaceOral doxycycline, metronidazole gel359CaucasianGrade 2 ER+, PR+, HER− w/ bone metsAbemaciclib8 monthsContinued at reduced doseN/AMorbilliform w/o mucosal erosionsProximal extremitiesTriamcinolone cream 0.1%, 0.025% capsaicin475CaucasianGrade 2 ER+, PR+, HER2− w/ node and lung metsPalbociclib13 monthsSwitched to abemaciclib3 monthsContinued abemaciclibInflamed actinic keratosesPhotodistributedTriamcinolone ointment 0.1%565Caucasian1. Invasive ductal, ER+2. Grade 3ER−, PR−, HER2 2:13. ER+, PR+. HER2− w/ bone metsPalbociclib10 monthsContinued at reduced doseN/ADermatitis (papular)PerioralMetronidazole cream 0.75%662African AmericanGrade 3 ER+, PR+, HER2−Palbociclib3 monthsSelf-weaned, started abemaciclib 5 years later21 daysDiscontinued abemaciclibPsoriasiform w/pustulosisExtremitiesTrunkPalmoplantarMethylprednisolone taper, clobetasol cream759CaucasianT2G2N0 retroperitoneal myxoid liposarcoma, recurrentPalbociclib1 yearDiscontinuedN/APustulosisPalmoplantarBetamethasone dipropionate ointment 0.05%, saltwater soaks869CaucasianER+, PR+, HER2− w/ bone metsPalbociclib11 monthsHeld, then continued after rash txN/AErosive pustular dermatitisScalpBetamethasone dipropionate ointment 0.05%934CaucasianT3N0 Stage IIB G2 ER+, PR−, HER2− w/ bone metsPalbociclibN/ASwitched to abemaciclib because of disease progression1.5 monthsContinued abemaciclibDermatitisPalmarParaffin wraps1085CaucasianT2N2a ER+, PR+, HER2− w/ pectoral muscle and lymph node metsPalbociclib8 monthsHeld for 1 month until evaluated by dermatologyN/ADermatitisPalmoplantarUrea cream 40%CDKi, Cyclin-dependent kinase inhibitor; ER, estrogen receptor; G, grade of primary tumor; HER2, human epidermal growth factor 2; IHC, immunohistochemistry; mets, metastasis; N, regional lymph nodes; N/A, not applicable; PR, progesterone receptor; T, primary tumor; Tx, treatment; W/, with; W/o, without. Open table in a new tab CDKi, Cyclin-dependent kinase inhibitor; ER, estrogen receptor; G, grade of primary tumor; HER2, human epidermal growth factor 2; IHC, immunohistochemistry; mets, metastasis; N, regional lymph nodes; N/A, not applicable; PR, progesterone receptor; T, primary tumor; Tx, treatment; W/, with; W/o, without. Palbociclib was the initial CDK4/6i used in 9 of the 10 cases and abemaciclib the initial agent in 1. The average time between drug initiation and the report of a cutaneous reaction was 6.8 months, with a range of 21 days to 13 months. The morphology of the reactions included morbilliform eruptions with mucosal erosions, inflamed actinic keratoses (AKs), psoriasiform dermatitis with or without pustulosis, pustular dermatoses, and palmoplantar dermatitis (Fig 1). In majority of the cases, the CDK4/6i doses were maintained, reduced, or discontinued. Of the 10 patients included in the series, 7 were able to resume CDK4/6i therapy after the treatment of the rash. Two patients (patients 4 and 6) were switched from palbociclib to abemaciclib after the development of cutaneous toxicity and subsequently experienced the development of a similar cutaneous reaction to abemaciclib. These findings suggest a potential class effect of CDK4/6i. A limitation is that several of the reactions reported here may have occurred by coincidence and not directly due to CDK4/6i. Four patients presented with pustular morphologies, including palmoplantar pustulosis and psoriasiform dermatitis with pustulosis. Although the exact role of CDK4/6 in psoriasis is not understood, the epidermis in humans with psoriasis has been shown to have increased CDK4 levels.4Henri P. Prevel C. Pellerano M. et al.Psoriatic epidermis is associated with upregulation of CDK2 and inhibition of CDK4 activity.Br J Dermatol. 2020; 182: 678-689Crossref PubMed Scopus (12) Google Scholar In addition, 1 patient appeared to have inflamed AKs. Normally, p16 complexes with and inactivates CDK4/6. p16 mutations are present in AKs, thereby preventing the inactivation of CDK4/6 and promoting carcinogenesis.5Hodges A. Smoller B.R. Immunohistochemical comparison of p16 expression in actinic keratoses and squamous cell carcinomas of the skin.Mod Pathol. 2002; 15: 1121-1125Crossref PubMed Scopus (90) Google Scholar This may explain why exogenous inhibition using a CDK4/6i leads to AK inflammation. The agents used to treat these adverse cutaneous reactions represent commonly prescribed therapeutics in the field of dermatology, except for methylprednisolone, and have low adverse effect profiles. Additionally, they are cost-effective options readily available to most practitioners, suggesting the ease and affordability of treating patients based on their condition and continuing oncologic therapy. As 7 patients were able to resume CDK4/6i therapy, one can conclude that majority of the treatments used were effective. Understanding the potential morphology and distribution of CDK4/6i-induced cutaneous reactions allows for faster recognition, accurate diagnosis, and appropriate therapeutic management to continue oncologic therapies, leading to more favorable outcomes. None disclosed.