Keeping abreast of drug-induced cutaneous lupus

By Warren R. Heymann, MD, FAAD
Aug. 4, 2021
Vol. 3, No. 31

Tom Hanks, as Commander Jim Lovell in the movie Apollo 13, lamented that the world was not watching their onboard video, compared to Neil Armstrong’s moon landing a year earlier. Reality dictates that the seminal breakthroughs demand attention; in the case of drug-induced cutaneous lupus, medical dermatologists took notice in 1985 when Reed et al reported the association of hydrochlorothiazide with subacute cutaneous lupus erythematosus (SCLE) in five patients. (1) Over the past 35 years, more than 40 drugs have been implicated as triggers of SCLE, most notably terbinafine, calcium channel blockers, angiotensin-converting enzyme inhibitors, tumor necrosis factor- alpha inhibitors, and chemotherapeutic agents. (2) While new associations may not generate “buzz,” when a class of agents starts to be increasingly reported with cutaneous lupus, dermatologists must take notice, as such associations may further understanding of the pathophysiology of lupus itself. This commentary will focus on recent reports of cutaneous lupus with CDK4/6 inhibitors.

Activation of cyclin-dependent kinase 4 (CDK4) and cyclin-dependent kinase 6 (CDK6) have been implicated in cell proliferation and resistance to therapy. (3) Inhibition of CDK 4 and 6 will prevent the phosphorylation of retinoblastoma protein, thereby blocking cell cycle progression from G1 to S phases. (4) Additionally, these drugs lead to increased T-cell activation by enhancing checkpoint inhibition. (5) The CCK4/6 inhibitors — palbociclib (Ibrance), ribociclib (Kisqali) and abemaciclib (Verzenio) — are well-tolerated, only rarely causing a “rash.” (3) These drugs are indicated for hormone receptor-positive, HER2 negative, advanced, progressive, or metastatic breast cancer. These agents are characteristically prescribed in concert with fulvestrant (an estrogen receptor antagonist), letrozole (an aromatase inhibitor), or an LHRH agonist (in pre/perimenopausal women or in men). (6)

The first case of SCLE induced by palbociclib was reported by Pinard et al in a 50+ year-old woman who received the drug with fulvestrant for her stage IIb breast cancer diagnosed a decade earlier. The diagnosis of SCLE was confirmed histologically; the lesions resolved within a month of discontinuation of palbociclib, while remaining on fulvestrant. Other than a minimally elevated ANA, her lupus serologies were negative. (4) A second case of SCLE associated with palbociclib was in a 73-year-old woman with ER+ HER2- metastatic breast cancer, status post chemotherapy, who developed biopsy-proven SCLE five weeks after administration of palbociclib and letrozole, accompanied by a positive ANA and SS-A, but negative dsDNA. The rash resolved within a month of discontinuation of palbociclib (with concurrent use of triamcinolone), while she was maintained on letrozole. (7)

Biopsy-proven chronic cutaneous (discoid) lupus has been linked to palbociclib in two reports of women with stage IV breast cancer — a 45-year-old woman with a positive ANA and anti-SSA antibodies (5) and a 70-year-old woman whose lupus serologies were negative. Lesions resolved in both patients upon discontinuation of the drug (with high potency topical steroids). Palbociclib was reintroduced to the 70-year-old patient three months later for better control of her metastatic disease; two weeks later, her lupus lesions recurred, further substantiating the association of the drug with lupus. (8)

Although the pathomechanism for CDK4/6 inhibitors to induce lupus is unknown, CDK1 is a positive regulator of the interferon signaling pathway, considered to be pathogenic in lupus. (9) Perhaps the inhibitors are influencing interferon production. Other potential mechanisms could include enhanced checkpoint inhibition or increased apoptosis leading to nucleosome release, thereby triggering autoimmunity. (5)

Although it is difficult to reach conclusions based on four case reports, should I encounter patients with CDK4/6 inhibitor-induced cutaneous lupus, I will leave it at the discretion of the oncologist to decide if the drug should be discontinued. Potent topical steroids will be utilized as first-line therapy and hydroxychloroquine secondarily (hydroxychloroquine was prescribed in reference 4, but never administered). Recurrence of lupus may be expected in the event the CDK4/6 inhibitor is discontinued but subsequently re-administered.

As for any new class of drugs, it is probable that their use will expand beyond initial indications. Palbociclib shows promise (as mono or combined therapy) in myeloma, non-Hodgkin lymphoma, lung cancer, colorectal cancer, and melanoma. (9) The likelihood of dermatologists diagnosing lupus in these patients will increase with novel indications. Clinicians must be cognizant of the association of CDK4/6 inhibitors and cutaneous lupus — as stated in Apollo 13, failure to do so is not an option.

Point to Remember: Cyclin-dependent kinase 4/6 inhibitors have recently been introduced for patients with advanced, progressive or metastatic breast cancer. There are an increasing number of reports associating these drugs with cutaneous lupus — both chronic (discoid) lupus and subacute cutaneous lupus. Dermatologists are likely to observe these cases as the indications for these drugs expand.

Our expert’s viewpoint

Generosa Grana, MD
Professor of Medicine
Director of the MD Anderson Cancer Center at Cooper

The evolving role of CDK4/6 inhibitors in breast cancer

While the CDK4/6 inhibitors have changed the face of treatment of women with metastatic breast cancer — in combination with a variety of endocrine agents such as aromatase inhibitors (letrozole, anastrazole and exemestane), fulvestrant, tamoxifen and LHRH agonists — the excitement in this area is the ongoing work as potential agents in the treatment of early stage breast cancer. Should these studies prove beneficial, the number of women who will be treated with these agents will significantly increase; thus, the importance of being aware of their potential for skin manifestations will be critical for dermatologists and oncologists.

The three agents in this group — abemaciclib (Verzenio), palbociclib (Ibrance) and ribociclib (Kisqali) — are all FDA approved in the first-line metastatic setting, combined with endocrine therapy, based on results of several Phase III clinical trials; abemaciclib is also approved as monotherapy. The impact of these agents is significant with an improvement in progression-free survival (PFS) of 14-25 months in the CDK4/6 + AI trials vs. 14-16 months with endocrine therapy alone. Several studies are evaluating these agents in the preoperative setting, as well as in the adjuvant setting with 3 large trials — MonarchE with abemaciclib (NCT03155997), PALLAS with palbociclib (NCT02513394), and NATALEE with ribociclib (NCT03701334). Although some preliminary data has already been presented, the full data is anxiously awaited by oncologists and patients alike. Also ongoing are studies combining these agents with a variety of other agents, including immunotherapy. (10)

Skin manifestations tend to not be major barriers for utilization of these drugs. Rash has been reported in 11-18% of patients on the pivotal trials, all being grade 1. The major toxicities of these compounds tend to be gastrointestinal toxicity (nausea, diarrhea, and vomiting) and bone marrow suppression. Grade 3 neutropenia has been reported in 22%, 60%, and 66% with abemaciclib, ribociclib, and palbociclib, respectively. Ribociclib is associated with QTc prolongation; EKG monitoring is required at the start of therapy and attention to potential drug and food interactions have to be considered. Based on the patients’ medical history, the spectrum of toxicity amongst the 3 agents is often used by oncologists to determine which drug to prescribe. This spectrum of toxicity is related to the relative potency of these agents — in particular whether one agent has greater inhibition of CDK 4 vs. 6. The inhibition of CDK 9 seen with abemaciclib is of ongoing interest (11,12).

Oncologists are learning to deal with the toxicities of this exciting new group of drugs. There is tremendous excitement about the presumed impact they will have on the lives of women with metastatic breast cancer and in the broader community of women with early stage disease.

Key clinical trials with CDK4/6 inhibitors:

Ribociclib:
Hortobagyi GN, Stemmer SM, Burris HA, Yap Y-S, Sonke GS, Paluch-Shimon S, et al. Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer. N Engl J Med. 2016;375:1738–48.

Slamon DJ, Neven P, Chia S, Fasching PA, De Laurentiis M, Im S-A, et al. Phase III Randomized Study of Ribociclib and Fulvestrant in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: MONALEESA-3. J Clin Oncol. 2018;36:2465–72.

Palbociclib:
Finn RS, Martin M, Rugo HS, Jones S, Im S-A, Gelmon K, et al. Palbociclib and Letrozole in Advanced Breast Cancer. N Engl J Med. 2016;375:1925–36.

Turner NC, Ro J, André F, Loi S, Verma S, Iwata H, et al. Palbociclib in Hormone- Receptor-Positive Advanced Breast Cancer. N Engl J Med. 2015;373:209–19.

Cristofanilli M, Turner NC, Bondarenko I, Ro J, Im S-A, Masuda N, et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor- positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol. 2016;17:425–39.

Abemaciclib:
Goetz MP, Toi M, Campone M, Sohn J, Paluch-Shimon S, Huober J, et al. MONARCH 3: Abemaciclib As Initial Therapy for Advanced Breast Cancer. J Clin Oncol. 2017;35:3638–46.

Sledge GW, Toi M, Neven P, Sohn J, Inoue K, Pivot X, et al. MONARCH 2: Abemaciclib in Combination With Fulvestrant in Women With HR+/HER2- Advanced Breast Cancer Who Had Progressed While Receiving Endocrine Therapy. J Clin Oncol. 2017;35:2875–84.

Verzenio^® (abemaciclib) significantly reduced the risk of cancer returning in people with high risk hr+, her2- early breast cancer. News release. Eli Lilly and Company. June 16, 2020. Accessed June 16, 2020. https://bit.ly/3fv2fq8.

1. Reed BR, Huff JC, Jones SK, et al. Subacute cutaneous lupus erythematosus in associated with hydrochlorothiazide therapy. Ann Intern Med 1985; 103: 49-51.

2. Grönhagen CM, Fored CM, Linder M, et al. Subacute cutaneous lupus erythematosus and its association with drugs: A population-based matched case-control study of 234 patients in Sweden. Br J Dermatol 2012; 167: 296-305.

3. Costa R, Costa RB, Talamantes SM, et al. Meta-analysis of selected toxicity endpoints of CDK4/6 inhibitors: Palbociclib and ribociclib. Breast 2017; 35: 1-7.

4. Pinard J, Patel M, Granter SR, et al. Subacute cutaneous lupus erythematosus induced by palbciclib. J Cutan Med Surg 2018; 22: 341-343.

5. Freedman JB, Herkovitz I, Maderal AD. Chronic cutaneous lupus erythematosus (discoid lupus) induced by palbociclib. Int J Dermatol 2020; 59: e195-e224.

6. Epocrates (accessed August 8, 2020).

7. Russell-Goldman E, Nazarian RM. Subacute cutaneous lupus erythematosus with positive anti-Ro antibodies following palbociclib and letrozole treatment: A case report and literature review. J Cutan Pathol 2020; 47: 654-658.

8. Calabrese G, Licata G, Gambardella A, et al. A case of discoid lupus erythematosus because of palbociclib. J Cutan Pathol 2020: 47: 668-670.

9. Liu M, Liu H, Chen J. Mechanisms of the CDK4/6 inhibitor palbociclib (PD 0332991) and its future application in cancer treatment (Review). Oncol Rep 2018;39(3):901-911.

10. Spring LM, Wander SA, Zangardi M, Bardia A. CDK 4/6 Inhibitors in Breast Cancer: Current Controversies and Future Directions. Curr Oncol Rep. 2019;21(3):25. Published 2019 Feb 26. doi:10.1007/s11912-019-0769-3

11. Marra, A., Curigliano, G. Are all cyclin-dependent kinases 4/6 inhibitors created equal?. npj Breast Cancer 5, 27 (2019). https://doi.org/10.1038/s41523-019-0121-y

12. Klein M., Kovatcheva M., et al. CDK4/6 inhibitors: The mechanism of action may not be as simple as once thought. Cancer Cell. 2018 Jul 9; 34(1): 9–20. Published online 2018 May 3. doi: 10.1016/j.ccell.2018.03.023

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