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Emerging nail reactions to anti‐cancer therapy
Anisha B. Patel, M.D.Assistant Professor, DermatologyUT MD Anderson Cancer Center
UT Health Science Center‐ Houston
Outline and Objectives
• Background: cytotoxic versus targeted cancer therapies
• Nail reactions to cytotoxic chemotherapy
• Nail reactions to novel cancer therapies
BackgroundCytotoxic chemotherapy
• Target rapidly replicating cells
• Hair: Anagen effluvium
• Skin: Toxic erythema
• Nails: Onycholysis, Beau’s lines, Pigmentation change
Targeted therapies
• Targeted inhibition of small molecules
• Emergence in 1990s
• Higher efficacy for cancer treatment
• Decreased systemic toxicities
• New hair, skin, nail toxicities
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Legend• Erlotinib, Gefitinib, Cetuximab• Sorafenib, Sunitinib, Regorafenib• Trametinib, Selumetinib• Vemurafenib, Dabrafenib• Lapatinib, Trastuzumab, Pertuzumab• Sirolimus, Everolimus, Temsirolimus• Pazopanib, Regorafenib• Vandetanib• Dasatanib, Nilotinib, Ponatinib
• EGFR inhibitors• Multikinase inhibitors• MEK inhibitors• BRAF inhibitors• HER2 inhibitors• mTOR inhibitors• VEGF inhibitors• RET inhibitors• Bcr‐Abl TKIs (2nd & 3rd gen)
Legend• CTLA4 inhibitors• Ipilimumab‐ Mar 2011, metastatic melanoma• Tremelimumab‐ failed Phase III trials
• PD‐1 inhibitors• Nivolumab‐ Dec 2014, metastatic melanoma• Pembrolizumab‐ Sep 2014, metastatic melanoma
• PD‐L1 inhibitors• Atezolizumab‐ May 2016, urothelial carcinoma• Avelumab‐ Phase III trials• Durvalumab‐ Phase III trials
Background
Piraccini BM, Alessandrini A. Drug‐related nail disease. Clinics in Dermatology (2013) 31, 618–626.
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Beau’s lines
• Pathogenesis: Proximal nail matrix
• Clinical presentation: Transverse depressions of the surface of the nail – depth indicates damage to the matrix
– length indicates the insult’s duration
• Causative chemo:– Any cytotoxic chemotherapy
https://www.dermnetnz.org/imagedetail/7335
True transverse leukonychia• Pathogenesis: Distal nail
matrix– Persistence of cell nuclei in the
nail plate ‐> reflects light
• Clinical presentation: Transverse opaque white bands
– Affects all nails at the same level
– Moves distally with nail growth
• Causative chemo:– Doxorubicin, cyclophosphamide,
and vincristine http://www.dermnetnz.org/imagedetail/7337
Onychomadesis• Pathogenesis: Proximal nail
matrix• Clinical presentation: Shedding
of the nail or a sulcus that splits the nail plate – Begins at the proximal nail fold– Extreme degree of Beau’s lines
• Causative chemo:– Any cytotoxic chemotherapy– EGFR inhibitors
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Onycholysis
• Pathogenesis: Nail bed epithelium
– Dose related
– Photo‐induced (thumbs spared)
• Clinical presentation: Loss of the nail plate and loss of nail bed adhesion
– Appears white
Onycholysis
• Causative chemo:– Taxanes (docetaxel and paclitaxel)
– PD1 inhibitors
– Tetracyclines and psoralen (photo)
• Complications:– Subungual abscesses
No photo‐onycholysis for targeted (yet)
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Paronychia and Periungual pyogenic granuloma
• Pathogenesis: Nail folds
• Clinical presentation: Nail folds erythematous, swollen, and painful
– Involvement of several nails of both the fingers and the toes
• Causative chemo:
– Taxanes, capecitabine, systemic retinoids, antiretrovirals
– EGFR inhibitors, MEK inhibitors, mTOR inhibitors
• Mechanism
– EGFR expressed in undifferentiated basal keratinocytes
– Blockade causes • Early differentiation (increased KRT1, STAT3, p27)
• Decreased replication (downregulated Ki67, MAPK)
• Increased inflammatory cytokines ‐> apoptosis
– Thin stratum corneum, abnormally differentiated epidermis, dyskeratosis
– Follicular rupture ‐> Inflammation and Pustules
Lacouture ME. Mechanisms of cutaneous toxicities to EGFR inhibitors. Nat Rev Cancer. 2006;6(10):803‐12.
Paronychia and Periungual PG
• EGFR inhibitors
• MEK inhibitors
• mTOR inhibitors
Paronychia and Periungual PG
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Nail fragility• Pathogenesis: Alteration of the nail plate production
– Superficial nail fragility: proximal nail matrix– Thin brittle plate: diffuse damage to the nail matrix
• Clinical presentation:– Onychoschizia: upper layers of the plate are detached – Elkonyxis: fragility of the surface of the proximal part of the plate– Onychorrhexis: ridging of the nail plate
• Causative chemo:– EGFR inhibitors, MEK inhibitors, mTOR inhibitors, PD1 inhibitors
• Complications: Ingrown toenails and pyogenic granuloma
Onychoschizia
Onychoschizia
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Onychorrhexis
Onychorrhexis and onychoschyzia
• Ibrutinib (CD20 targeted inhibitor)
– 66 study participants
– 55 to 85 years old
– 43 men and 23 women
– 44 (67%) with new‐onset fingernail changes (median 6.5 months)
– 15 (23%) with brittle toenails (median 9 months)
– mild to moderate onychoschizia and onychorrhexis, Grade 1 and 2
Bitar C, FarooquiMZ, Valdez J, et al. Hair and Nail Changes During Long‐term Therapy With Ibrutinib for Chronic Lymphocytic Leukemia. JAMA Dermatol. 2016;152(6):698‐701.
Splinter subungual hemorrhage
• Clinical presentation: – Asymptomatic red, brown, or
black longitudinal lines
• Causative chemo: – VEGFR inhibitors
http://www.regionalderm.com/Regional_Derm/RD_Large/Splinter_hemor.jpg
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Pigmentation• Pathogenesis: Distal matrix activation of melanocytes
• Clinical presentation:– Longitudinal melanonychia
– Transverse melanonychia
• Causative chemo:– Doxorubicin, bleomycin, cyclophosphamide, daunorubicin, dacarbazine, 5‐fluorouracil,
methotrexate, and hydroxyurea
– Transverse melanonychia: electron beam therapy, radiation therapy, psoralen with ultraviolet A, infliximab
– Bcr‐Abl tyrosine kinase inhibitors (imatinib), BRAF inhibitors
Melanocytic neoplasms
• BRAF inhibitors
Melanocytic neoplasms
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Psoriasiform dermatitis
• PD‐1 inhibitors
Psoriasiform dermatitis
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Psoriasiform dermatitis
• PD‐1 inhibitors
Lichenoid dermatitis• CTLA4 inhibitors
• PD‐1 inhibitors
Lichenoid dermatitis
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Lichenoid dermatitis• CTLA4 inhibitors
• PD‐1 inhibitors
http://www.dermnetnz.org/topics/lichen‐planus‐nail‐images/
Summary
• Targeted inhibitors and immune therapies have overlapping nail reactions with cytotoxic chemotherapies– Onychomadesis, onycholysis, paronychia, nail fragility, melanonychia,
• Some can be dose limiting – Paronychia, pyogenic granuloma
• Inflammatory and neoplastic cutaneous toxicities can have classic nail manifestations/toxicities– Psoriasis, lichen planus
• Future questions: predictive of tumor response or further, more severe adverse events?
References• Berthod G, Lazor R, Letovanec I, et al. Pulmonary sarcoid‐like granulomatosis induced by ipilimumab. J Clin Oncol. 2012;30(17):e156‐9.
• Coutinho I, Pereira N, Gouveia M, Cardoso JC, Tellechea O. Interstitial Granulomatous Dermatitis: A Clinicopathological Study. Am J Dermatopathol. 2015;37(8):614‐9.
• Eckert A, Schoeffler A, Dalle S, Phan A, Kiakouama L, Thomas L. Anti‐CTLA4 monoclonal antibody induced sarcoidosis in a metastatic melanoma patient. Dermatology (Basel). 2009;218(1):69‐70.
• Garrido MC, Gutierrez C, Riveiro‐falkenbach E, Ortiz P, Rodriguez‐peralto JL. BRAF Inhibitor‐Induced Antitumoral Granulomatous Dermatitis Eruption in Advanced Melanoma. Am J Dermatopathol. 2015;37(10):795‐8.
• Jansen YJ, Janssens P, Hoorens A, et al. Granulomatous nephritis and dermatitis in a patient with BRAF V600E mutant metastatic melanoma treated with dabrafenib and trametinib. Melanoma Res. 2015;25(6):550‐4.
• Lacouture ME, Wolchok JD, Yosipovitch G, Kähler KC, Busam KJ, Hauschild A. Ipilimumab in patients with cancer and the management of dermatologic adverse events. J Am Acad Dermatol. 2014;71(1):161‐9.
• Luke JJ, Lezcano C, Hodi FS, Murphy GF. Antitumor granuloma formation by CD4+ T cells in a patient with rapidly progressive melanoma experiencing spiking fevers, neuropathy, and other immune‐related toxicity after treatment with ipilimumab. J Clin Oncol. 2015;33(6):e32‐5.
• Park JJ, Hawryluk EB, Tahan SR, Flaherty K, Kim CC. Cutaneous granulomatous eruption and successful response to potent topical steroids in patients undergoing targeted BRAF inhibitor treatment for metastatic melanoma. JAMA Dermatol. 2014;150(3):307‐11.
• Suozzi KC, Stahl M, Ko CJ, et al. Immune‐related sarcoidosis observed in combination ipilimumab and nivolumab therapy. JAAD Case Rep. 2016;2(3):264‐8.
• Toumeh A, Sakhi R, Shah S, Arudra SK, De las casas LE, Skeel RT. Ipilimumab‐Induced Granulomatous Disease Occurring Simultaneously With Disease Progression in a Patient With Metastatic Melanoma. Am J Ther. 2016;23(4):e1068‐71.
• Vogel WV, Guislain A, Kvistborg P, Schumacher TN, Haanen JB, Blank CU. Ipilimumab‐induced sarcoidosis in a patient with metastatic melanoma undergoing complete remission. J Clin Oncol. 2012;30(2):e7‐e10.
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References• Parma J, Pavlick A, Schiff R, et al. Development of acneiform rash does not predict response to lapatinib treatment in patients with breast cancer.
Pharmacotherapy. 2013;33(10):1126‐9.
• Lee Y, Shim HS, Park MS, et al. High EGFR gene copy number and skin rash as predictive markers for EGFR tyrosine kinase inhibitors in patients with advanced squamous cell lung carcinoma. Clin Cancer Res. 2012;18(6):1760‐8.
• Jonker DJ, O'callaghan CJ, Karapetis CS, et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007;357(20):2040‐8.
• Klinghammer K, Knödler M, Schmittel A, Budach V, Keilholz U, Tinhofer I. Association of epidermal growth factor receptor polymorphism, skin toxicity, and outcome in patients with squamous cell carcinoma of the head and neck receiving cetuximab‐docetaxel treatment. Clin Cancer Res. 2010;16(1):304‐10.
• Cohen EE, Halpern AB, Kasza K, Kocherginsky M, Williams R, Vokes EE. Factors associated with clinical benefit from epidermal growth factor receptor inhibitors in recurrent and metastatic squamous cell carcinoma of the head and neck. Oral Oncol. 2009;45(10):e155‐60.
• Huang CL, Yang CH, Yeh KH, et al. EGFR intron 1 dinucleotide repeat polymorphism is associated with the occurrence of skin rash with gefitinib treatment. Lung Cancer. 2009;64(3):346‐51.
• Parmar S, Schumann C, Rüdiger S, et al. Pharmacogenetic predictors for EGFR‐inhibitor‐associated skin toxicity. Pharmacogenomics J. 2013;13(2):181‐8.
• Peréz‐soler R, Saltz L. Cutaneous adverse effects with HER1/EGFR‐targeted agents: is there a silver lining?. J Clin Oncol. 2005;23(22):5235‐46.
• Zaborowska‐szmit M, Kowalski DM, Piórek A, Krzakowski M, Szmit S. A decrease in D‐dimer concentration and an occurrence of skin rash as iatrogenic events and complementary predictors of survival in lung cancer patients treated with EGFR tyrosine kinase inhibitors. Pharmacol Rep. 2016;68(6):1140‐1148.
• Kudo K, Hotta K, Bessho A, et al. Development of a skin rash within the first week and the therapeutic effect in afatinib monotherapy for EGFR‐mutant non‐small cell lung cancer (NSCLC): Okayama Lung Cancer Study Group experience. Cancer Chemother Pharmacol. 2016;77(5):1005‐9.
References• Sugiura Y, Nemoto E, Kawai O, Ohkubo Y, Fusegawa H, Kaseda S. Skin rash by gefitinib is a sign of favorable outcomes for patients of advanced lung
adenocarcinoma in Japanese patients. Springerplus. 2013;2(1):22.
• Petrelli F, Borgonovo K, Cabiddu M, Lonati V, Barni S. Relationship between skin rash and outcome in non‐small‐cell lung cancer patients treated with anti‐EGFR tyrosine kinase inhibitors: a literature‐based meta‐analysis of 24 trials. Lung Cancer. 2012;78(1):8‐15.
• Wacker B, Nagrani T, Weinberg J, Witt K, Clark G, Cagnoni PJ. Correlation between development of rash and efficacy in patients treated with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in two large phase III studies. Clin Cancer Res. 2007;13(13):3913‐21.
• Liu HB, Wu Y, Lv TF, et al. Skin rash could predict the response to EGFR tyrosine kinase inhibitor and the prognosis for patients with non‐small cell lung cancer: a systematic review and meta‐analysis. PLoS ONE. 2013;8(1):e55128.
• Agulnik M, Da cunha santos G, Hedley D, et al. Predictive and pharmacodynamic biomarker studies in tumor and skin tissue samples of patients with recurrent or metastatic squamous cell carcinoma of the head and neck treated with erlotinib. J Clin Oncol. 2007;25(16):2184‐90.
• Kim JH, Choi YJ, Lee BH, et al. Programmed cell death ligand 1 alleviates psoriatic inflammation by suppressing IL‐17A production from programmed cell death 1‐high T cells. J Allergy Clin Immunol. 2016;137(5):1466‐1476.e3.