CASE REPORT
Eruptive Squamous Cell Carcinomas after Vemurafenib Therapy Rana Mays, Jonathan Curry, Kevin Kim, Kenneth Tsai, Anita Arora, Farhan Khan, Marigdalia Ramirez-Fort, and Ana Ciurea
Background: Vemurafenib is an oral BRAF inhibitor recently approved for the treatment of metastatic melanoma. Patients treated with this medication have been reported to have the occurrence of squamous cell carcinoma (SCC) and/or actinic keratosis (AK). Objective: We report the case of a patient treated with vemurafenib for papillary thyroid carcinoma who subsequently developed multiple SCCs and AK of the skin. The lesions were deemed related to the medication and treated with excision. In addition, subsequent development of SCCs and AK was successfully prevented with a combination of isotretinoin and 5-fluorouracil in this patient. We discuss postulated mechanisms for these findings, as well as potential preventive therapy with the aforementioned combination regimen in patients undergoing treatment with vemurafenib. Contexte: Le ve´murafe´nib est un inhibiteur oral de la prote´ine BRAF, approuve´ dernie`rement dans le traitement du me´lanome me´tastatique. L’apparition de le´sions de carcinome a` cellules squameuses (CS) et/ou de ke´ratose actinique (KA) a de´ja` e´te´ signale´e chez des patients traite´s par ce me´dicament. Objectif: Sera de´crit ici le cas d’un patient traite´ par le ve´murafe´nib pour un carcinome papillaire de la thyroı¨de, chez qui sont apparues plus tard de nombreuses le´sions de CS de la peau et de KA. On a juge´ que ces le´sions e´taient lie´es au me´dicament, et elles ont e´te´ traite´es par exe´re`se. Par ailleurs, l’association d’isotre´tinoı¨ne et de 5-fluoro-uracile a permis de pre´venir efficacement l’apparition ulte´rieure d’autres le´sions de CS et de KA chez ce patient. Il sera question des me´canismes mis de l’avant pour expliquer l’apparition de ces le´sions ainsi que de la the´rapie potentiellement pre´ventive, compose´e des me´dicaments mentionne´s plus haut, chez les patients devant eˆtre traite´s par le ve´murafe´nib.
V
EMURAFENIB (Zelboraf, Hoffmann-La Roche, Basel, Switzerland) is an oral, highly potent BRAF inhibitor recently approved by the Food and Drug Administration (FDA) and Health Canada (HC) for the treatment of metastatic melanoma in patients with V600E BRAF mutation. Early-phase clinical trials, as well as the phase III clinical trial that led to the FDA and HC approval, have reported a higher incidence of actinic keratosis (AK) and keratoacanthoma (KA) or squamous
cell skin carcinoma (SCC) during treatment with vemurafenib.1 Molecular analysis has identified activating mutations in BRAF in papillary thyroid cancer (PTC). Mutant BRAF in PTC, similar to mutant BRAF in melanoma, activates the mitogen-activated protein kinase (MAPK) signal transuction pathway. Targeted therapies for advanced thyroid tumors are currently in clinical trials.2 Here we report the development of multiple cutaneous keratinocytic eruptions diagnosed as SCCs in a patient treated with vemurafenib for PTC.
From the Center for Clinical Studies, Houston, TX; Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, TX; Department of Dermatology, University of Texas Medical School at Houston, Houston, TX; Department of Dermatology, Tufts Medical Center, Boston, MA.
Case Report
Address reprint requests to: Rana Mays, MD, Center for Clinical Studies, 1401 Binz, Suite 200, Houston, TX 77004; e-mail: [email protected].
DOI 10.2310/7750.2013.12092 # 2013 Canadian Dermatology Association
A 57-year-old man without a history of cutaneous SCC and AK diagnosed with PTC underwent total thyroidectomy followed by radioactive iodine therapy in 1999. He had multiple invasive recurrences involving bilateral neck, right supraclavicular, and superior mediastinal lymph nodes until 2007, and he underwent extensive lymph node dissections of involved regions. However, the patient’s
Canadian Dermatology Association | Journal of Cutaneous Medicine and Surgery, Vol 17, No 6 (November/December), 2013: pp 419–422
419
Mays et al
disease progressed, and approximately 1 year later, the patient was found to have local recurrence involving the thyroid bed with mediastinal and axillary nodal metastases. Because of the limited efficacy of conventional chemotherapy for advanced thyroid cancer, the patient was enrolled in a phase I clinical trial of vemurafenib. He was initially started on 240 mg of vermurafenib twice a day and subsequently increased to 360 mg twice a day after six cycles (one cycle 5 4 weeks) because he tolerated the initial dose without significant adverse events. Because of good tolerance, the dose was subsequently increased to 720 mg of vermurafenib twice daily after five cycles on a 360 mg twice-daily dose. Approximately 8 months after starting vemurafenib treatment, he presented to his primary care physician with an invasive, well-differentiated SCC (3 mm thickness) on the right upper back (Figure 1A), which was excised. The patient was referred to the Department of Dermatology at the University of Texas MD Anderson Cancer Center for further evaluation and treatment of the skin cancers. During therapy with vermurafenib, he developed numerous new cutaneous keratinocytic proliferates that were hyperkeratotic papules and nodules, located on the left thigh, left neck (Figure 1, B and C), left shoulder, left upper lip, left scalp, and right retroauricular area. The pathologic evaluation of all lesions revealed invasive SCC. Lesions demonstrated similar morphologic features and consisted of hyperkeratotic, cratiform, endophytic proliferation of atypical keratinocytes that were well- to moderately differentiated squamous cells invading into the dermis without perineural invasion. The epidermis was acanthotic and hyperkeratotic. Mitoses, including atypical mitotic figures, were readily identified. The architectural pattern was reminiscent of KA; however, the base of the lesion was infiltrative (Figure 2 and Figure 3, SCC from the right shoulder). The patient also developed AK that were clinically diagnosed on the left superior eyebrow, left parietal scalp, and right neck; a verruca vulgaris (VV) was noted on the left cheek. The patient’s SCCs were successfully excised; his AK and VV were treated with cryotherapy. The patient was allowed to continue vemurafenib under close observation and was started on oral isotretinoin (Accutane, Roche Laboratories, Basel, Switzerland) 10 mg daily in combination with topical 5-fluorouracil 5% cream (Efudex, Valeant Pharmaceuticals, Montreal, PQ) twice daily and a strict sun protection regimen to reduce further development of SCCs and/or AK. During this treatment, no further occurrence of any cutaneous SCC or AK lesions was observed during 6 more months of treatment with vemurafenib. Vemurafenib was ultimately discontinued 420
Figure 1. Eruptive cutaneous squamous cell carcinomas and actinic ketatoses during treatment with vemurafenib. A, Squamous cell carcinoma, right upper back. B, Squamous cell carcinoma, keratoacanthoma-like, left lateral thigh. C, Squamous cell carcinoma, left lateral neck.
after 14 cycles due to disease progression. After discontinuation of the drug, the patient continued to be followed and remained free from development of any new AK and/or SCCs; furthermore, his previous AK lesions started to regress. He subsequently underwent laryngectomy with
Canadian Dermatology Association | Journal of Cutaneous Medicine and Surgery, Vol 17, No 6 (November/December), 2013: pp 419–422
Eruptive SCCs after Vemurafenib Therapy
Figure 2. Cratiform, endophytic tumor nodule composed of well- to moderately differentiated, invasive, keratinizing squamous cells connected to a hyperkeratotic and acanthotic epidermis (hematoxylineosin stain; 320 original magnification).
radical neck dissection and remained clear of both SCC and AK 18 months after treatment was discontinued.
Discussion SCCs have been occasionally associated with targeted antineoplastic therapies.3–6 Vemurafenib, recently approved by the FDA and HC for the treatment of metastatic melanoma, inhibits the BRAF V600E mutated protein. The BRAF protein belongs to the Raf family of serine/threonine protein kinases and plays an important role in regulating the MAPK/extracellular signal–regulated (ERK) signaling pathway, which controls cell division, proliferation, and differentiation.7 Oncogenic mutations in the protein have been shown to alter the kinase domain and cause constitutive activation of the kinase.8 The V600E allele mutation results in an amino acid change of valine to glutamic acid at residue 600, resulting in constitutive
activation and increased cell division in melanocytes, colonic mucosa, and thyroid cells.9 BRAF mutations are found in approximately 55 to 60% of melanomas and 30% of colon cancers and serve as the most common genetic alteration in thyroid cancer, occurring in about 45% of sporadic PTCs.10–16 In a recent randomized trial, vemurafenib demonstrated improved survival in patients with malignant melanoma harboring the V600E BRAF mutation compared to dacarbazine.1 In addition to metastatic melanoma, vemurafenib has also been investigated for the treatment of other neoplasms associated with BRAF mutation, including PTC.17 Here we report the case of a patient treated with vemurafenib as investigational therapy for PTC who developed multiple cutaneous keratinocytic proliferations with the majority of the lesions diagnosed as SCCs and AK. The prevailing hypothesis for the development of SCC and/or AK with vemurafenib is that these lesions exhibit paradoxical activation of ERK signaling, which occurs to the greatest extent in the presence of RAS mutations.18 Evidence for this mechanism includes the apparent enrichment for RAS mutations in SCC/KA that arise in vemurafenib-treated patients compared to lesions that arise in non–drug-treated patients.19,20 This case also highlights the association between BRAF inhibition with vemurafenib and the development of cutaneous keratinocytic proliferations. All-trans retinoic acid (ATRA) therapy has been successfully used for chemoprevention of SCCs in several studies.21–23 In a recent trial, Cheepala and colleagues compared the gene expression profiles of control skin to skin exposed to ATRA and concluded that ATRA’s mechanism involves targeting the BRAF signaling pathway.22 This patient’s lesions improved after starting isotretinoin and 5-fluorouracil 5% cream. Furthermore, this combination therapy successfully prevented the
Figure 3. A, Invasion of moderately differentiated squamous cells into the reticular dermis with an enlarged nucleus, prominent nucleoli, and intercellular bridges (inset, asterisk) (hematoxylineosin stain; 3400 original magnification). B, Mitoses (arrows) are present throughout the lesion, including atypical mitoses (inset) (hematoxylin-eosin stain; 3200 original magnification).
Canadian Dermatology Association | Journal of Cutaneous Medicine and Surgery, Vol 17, No 6 (November/December), 2013: pp 419–422
421
Mays et al
development of new AK or SCCs in our patient during a remaining 6 months of treatment with vemurafenib and for an 18-month treatment-free period. Further studies are needed to better understand the association and causality between the development of SCCs and/or AK with vemurafenib therapy. Treatment with ATRA could potentially target the BRAF pathway, thereby enhancing its physiologic differentiation on squamous epithelium. Our clinical results suggest that isotretinoin along with 5-fluorouracil may be successful in the treatment and prevention of SCC and AK in such patients, including for the growing number of patients who will be undergoing therapy with vemurafenib for malignant melanoma. Herein we report a case of vemurafenib therapy associated with the development of AK and SCCs that were successfully treated with isotretinoin and 5-fluorouracil. The combination treatment was effective in preventing further development of lesions for 24 months. Further studies are necessary to elucidate the efficacy of our proposed combination therapy in the prevention of AK and SCC development in other patients receiving vemurafenib therapy. Patients undergoing treatment with vemurafenib should be referred to a dermatologist for close monitoring and further treatment of lesions if they occur.
Acknowledgment Financial disclosure of authors and reviewers: None reported.
References 1. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364:2507–16, doi:10.1056/NEJMoa1103782. 2. Sherman SI. Targeted therapies for thyroid tumors. Mod Pathol 2011;24 Suppl 2:S44–52, doi:10.1038/modpathol.2010.165. 3. Lynch MC, Straub R, Adams DR. Eruptive squamous cell carcinomas with keratoacanthoma-like features in a patient treated with sorafenib. J Drugs Dermatol 2011;10:308–10. 4. Lee WJ, Lee JL, Chang SE, et al. Cutaneous adverse effects in patients treated with the multitargeted kinase inhibitors sorafenib and sunitinib. Br J Dermatol 2009;161:1045–51, doi:10.1111/ j.1365-2133.2009.09290.x. 5. Robert C, Mateus C, Spatz A, et al. Dermatologic symptoms associated with the multikinase inhibitor sorafenib. J Am Acad Dermatol 2009;60:299–305, doi:10.1016/j.jaad.2008.06.034. 6. Hong DS, Reddy SB, Prieto VG, et al. Multiple squamous cell carcinomas of the skin after therapy with sorafenib combined with tipifarnib. Arch Dermatol 2008;144:779–82, doi:10.1001/archderm.144.6.779.
422
7. Garnett MJ, Marais R. BRAF is a human oncogene. Cancer Cell 2004;6:313–9, doi:10.1016/j.ccr.2004.09.022. 8. Sala E, Mologni L, Truffa S, et al. BRAF silencing by short hairpin RNA or chemical blockade by PLX4032 leads to different responses in melanoma and thyroid carcinoma cells. Mol Cancer 2008; 6:751–9. 9. King AJ, Patrick DR, Batorsky RS, et al. Demonstration of a genetic therapeutic index for tumors expressing oncogenic BRAF by the kinase inhibitor SB-590885. Cancer Res 2006;(23):11100–5, doi:10.1158/0008-5472.CAN-06-2554. 10. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature 2002;417:949–54, doi:10.1038/nature00766. 11. Deng G, Bell I, Crawley S, et al. BRAF mutation is frequently present in sporadic colorectal cancer with methylated hMLH1, but not in hereditary nonpolyposis colorectal cancer. Clin Cancer Res 2004;10:191–5, doi:10.1158/1078-0432.CCR-1118-3. 12. Di Nicolantonio F, Martini M, Mollinari F, et al. Wild type BRAF is required for response to panitumumab in metastatic colorectal cancer. J Clin Oncol 2008;26:5668–70, doi:10.1200/JCO.2008.18.0786. 13. Chiosea S, Nijiforova M, Zuo H, et al. A novel complex BRAF mutation detected in solid variant of papillary thyroid carcinoma. Endocr Pathol 2009;20:122–6, doi:10.1007/s12022-009-9073-3. 14. Frasca F, Nucera C, Pellegriti G, et al. BRAF (V600E) mutation and the biology of papillary thyroid cancer. Endocr Relat Cancer 2008; 15:191–205, doi:10.1677/ERC-07-0212. 15. Rajagopalan H, Bardelli A, Lengauer C, et al. Tumorigenesis: RAF/ RAS oncogenes and mismatch-repair status. Nature 2002;418:934, doi:10.1038/418934a. 16. Tsai J, Lee JT, Wang W, et al. Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity. Proc Natl Acad Sci U S A 2008;105:3041–6, doi:10.1073/pnas.0711741105. 17. Flaherty K, Puzanov I, Sosmon J, et al. Phase I study of PLX4032: proof of concept for V600E mutation as therapeutic target in human caner. J Clin Oncol 2009;27:461. 18. Kaplan FM, Mastrangelo MJ, Aplin AE. The wrath of RAFs: rogue behavior of B-RAF kinase inhibitors. J Invest Dermatol 2010;130: 2669–71, doi:10.1038/jid.2010.177. 19. Oberholzer PA, Kee D, Dziunycz P, et al. RAS mutations are associated with the development of cutaneous squamous cell tumors in patients treated with RAF inhibitors. Clin Oncol 2012; 30:316–21, doi:10.1200/JCO.2011.36.7680. 20. Lacouture ME, Chapman PB, Ribas A, et al. Presence of frequent underlying RAS mutations in cutaneous squamous cell carcinomas and keratoacanthomas (cuSCC/KA) that develop in patients during vemurafenib therapy [abstract]. J Clin Oncol 2011;29 Suppl:8520. 21. Fabricius EM, Kruse-Boitschenko U, Schneeweiss U, et al. Model examination of chemoprevention with retinoids in squamous cell carcinomas of the head and neck region and suitable biomarkers for chemoprevention. Int J Oncol 2011 Jul 22. [Epub ahead of print] 22. Cheepala SB, Yin W, Syed Z, et al. Identification of the B-Raf/Mek/ Erk MAP kinase pathway as a target for all-trans retinoid acid during skin cancer promotion. Mol Cancer 2009;8:27, doi:10.1186/ 1476-4598-8-27. 23. Siddikuzzaman, , Guruvayoorappan C, Berlin Grace VM. All trans retinoic acid and cancer. Immunopharmacol Immunotoxicol 2011; 33:241–9, doi:10.3109/08923973.2010.521507.
Canadian Dermatology Association | Journal of Cutaneous Medicine and Surgery, Vol 17, No 6 (November/December), 2013: pp 419–422
Copyright of Journal of Cutaneous Medicine & Surgery is the property of Decker Publishing and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Eruptive Squamous Cell Carcinomas after Vemurafenib Therapy Rana Mays, Jonathan Curry, Kevin Kim, Kenneth Tsai, Anita Arora, Farhan Khan, Marigdalia Ramirez-Fort, and Ana Ciurea
Background: Vemurafenib is an oral BRAF inhibitor recently approved for the treatment of metastatic melanoma. Patients treated with this medication have been reported to have the occurrence of squamous cell carcinoma (SCC) and/or actinic keratosis (AK). Objective: We report the case of a patient treated with vemurafenib for papillary thyroid carcinoma who subsequently developed multiple SCCs and AK of the skin. The lesions were deemed related to the medication and treated with excision. In addition, subsequent development of SCCs and AK was successfully prevented with a combination of isotretinoin and 5-fluorouracil in this patient. We discuss postulated mechanisms for these findings, as well as potential preventive therapy with the aforementioned combination regimen in patients undergoing treatment with vemurafenib. Contexte: Le ve´murafe´nib est un inhibiteur oral de la prote´ine BRAF, approuve´ dernie`rement dans le traitement du me´lanome me´tastatique. L’apparition de le´sions de carcinome a` cellules squameuses (CS) et/ou de ke´ratose actinique (KA) a de´ja` e´te´ signale´e chez des patients traite´s par ce me´dicament. Objectif: Sera de´crit ici le cas d’un patient traite´ par le ve´murafe´nib pour un carcinome papillaire de la thyroı¨de, chez qui sont apparues plus tard de nombreuses le´sions de CS de la peau et de KA. On a juge´ que ces le´sions e´taient lie´es au me´dicament, et elles ont e´te´ traite´es par exe´re`se. Par ailleurs, l’association d’isotre´tinoı¨ne et de 5-fluoro-uracile a permis de pre´venir efficacement l’apparition ulte´rieure d’autres le´sions de CS et de KA chez ce patient. Il sera question des me´canismes mis de l’avant pour expliquer l’apparition de ces le´sions ainsi que de la the´rapie potentiellement pre´ventive, compose´e des me´dicaments mentionne´s plus haut, chez les patients devant eˆtre traite´s par le ve´murafe´nib.
V
EMURAFENIB (Zelboraf, Hoffmann-La Roche, Basel, Switzerland) is an oral, highly potent BRAF inhibitor recently approved by the Food and Drug Administration (FDA) and Health Canada (HC) for the treatment of metastatic melanoma in patients with V600E BRAF mutation. Early-phase clinical trials, as well as the phase III clinical trial that led to the FDA and HC approval, have reported a higher incidence of actinic keratosis (AK) and keratoacanthoma (KA) or squamous
cell skin carcinoma (SCC) during treatment with vemurafenib.1 Molecular analysis has identified activating mutations in BRAF in papillary thyroid cancer (PTC). Mutant BRAF in PTC, similar to mutant BRAF in melanoma, activates the mitogen-activated protein kinase (MAPK) signal transuction pathway. Targeted therapies for advanced thyroid tumors are currently in clinical trials.2 Here we report the development of multiple cutaneous keratinocytic eruptions diagnosed as SCCs in a patient treated with vemurafenib for PTC.
From the Center for Clinical Studies, Houston, TX; Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, TX; Department of Dermatology, University of Texas Medical School at Houston, Houston, TX; Department of Dermatology, Tufts Medical Center, Boston, MA.
Case Report
Address reprint requests to: Rana Mays, MD, Center for Clinical Studies, 1401 Binz, Suite 200, Houston, TX 77004; e-mail: [email protected].
DOI 10.2310/7750.2013.12092 # 2013 Canadian Dermatology Association
A 57-year-old man without a history of cutaneous SCC and AK diagnosed with PTC underwent total thyroidectomy followed by radioactive iodine therapy in 1999. He had multiple invasive recurrences involving bilateral neck, right supraclavicular, and superior mediastinal lymph nodes until 2007, and he underwent extensive lymph node dissections of involved regions. However, the patient’s
Canadian Dermatology Association | Journal of Cutaneous Medicine and Surgery, Vol 17, No 6 (November/December), 2013: pp 419–422
419
Mays et al
disease progressed, and approximately 1 year later, the patient was found to have local recurrence involving the thyroid bed with mediastinal and axillary nodal metastases. Because of the limited efficacy of conventional chemotherapy for advanced thyroid cancer, the patient was enrolled in a phase I clinical trial of vemurafenib. He was initially started on 240 mg of vermurafenib twice a day and subsequently increased to 360 mg twice a day after six cycles (one cycle 5 4 weeks) because he tolerated the initial dose without significant adverse events. Because of good tolerance, the dose was subsequently increased to 720 mg of vermurafenib twice daily after five cycles on a 360 mg twice-daily dose. Approximately 8 months after starting vemurafenib treatment, he presented to his primary care physician with an invasive, well-differentiated SCC (3 mm thickness) on the right upper back (Figure 1A), which was excised. The patient was referred to the Department of Dermatology at the University of Texas MD Anderson Cancer Center for further evaluation and treatment of the skin cancers. During therapy with vermurafenib, he developed numerous new cutaneous keratinocytic proliferates that were hyperkeratotic papules and nodules, located on the left thigh, left neck (Figure 1, B and C), left shoulder, left upper lip, left scalp, and right retroauricular area. The pathologic evaluation of all lesions revealed invasive SCC. Lesions demonstrated similar morphologic features and consisted of hyperkeratotic, cratiform, endophytic proliferation of atypical keratinocytes that were well- to moderately differentiated squamous cells invading into the dermis without perineural invasion. The epidermis was acanthotic and hyperkeratotic. Mitoses, including atypical mitotic figures, were readily identified. The architectural pattern was reminiscent of KA; however, the base of the lesion was infiltrative (Figure 2 and Figure 3, SCC from the right shoulder). The patient also developed AK that were clinically diagnosed on the left superior eyebrow, left parietal scalp, and right neck; a verruca vulgaris (VV) was noted on the left cheek. The patient’s SCCs were successfully excised; his AK and VV were treated with cryotherapy. The patient was allowed to continue vemurafenib under close observation and was started on oral isotretinoin (Accutane, Roche Laboratories, Basel, Switzerland) 10 mg daily in combination with topical 5-fluorouracil 5% cream (Efudex, Valeant Pharmaceuticals, Montreal, PQ) twice daily and a strict sun protection regimen to reduce further development of SCCs and/or AK. During this treatment, no further occurrence of any cutaneous SCC or AK lesions was observed during 6 more months of treatment with vemurafenib. Vemurafenib was ultimately discontinued 420
Figure 1. Eruptive cutaneous squamous cell carcinomas and actinic ketatoses during treatment with vemurafenib. A, Squamous cell carcinoma, right upper back. B, Squamous cell carcinoma, keratoacanthoma-like, left lateral thigh. C, Squamous cell carcinoma, left lateral neck.
after 14 cycles due to disease progression. After discontinuation of the drug, the patient continued to be followed and remained free from development of any new AK and/or SCCs; furthermore, his previous AK lesions started to regress. He subsequently underwent laryngectomy with
Canadian Dermatology Association | Journal of Cutaneous Medicine and Surgery, Vol 17, No 6 (November/December), 2013: pp 419–422
Eruptive SCCs after Vemurafenib Therapy
Figure 2. Cratiform, endophytic tumor nodule composed of well- to moderately differentiated, invasive, keratinizing squamous cells connected to a hyperkeratotic and acanthotic epidermis (hematoxylineosin stain; 320 original magnification).
radical neck dissection and remained clear of both SCC and AK 18 months after treatment was discontinued.
Discussion SCCs have been occasionally associated with targeted antineoplastic therapies.3–6 Vemurafenib, recently approved by the FDA and HC for the treatment of metastatic melanoma, inhibits the BRAF V600E mutated protein. The BRAF protein belongs to the Raf family of serine/threonine protein kinases and plays an important role in regulating the MAPK/extracellular signal–regulated (ERK) signaling pathway, which controls cell division, proliferation, and differentiation.7 Oncogenic mutations in the protein have been shown to alter the kinase domain and cause constitutive activation of the kinase.8 The V600E allele mutation results in an amino acid change of valine to glutamic acid at residue 600, resulting in constitutive
activation and increased cell division in melanocytes, colonic mucosa, and thyroid cells.9 BRAF mutations are found in approximately 55 to 60% of melanomas and 30% of colon cancers and serve as the most common genetic alteration in thyroid cancer, occurring in about 45% of sporadic PTCs.10–16 In a recent randomized trial, vemurafenib demonstrated improved survival in patients with malignant melanoma harboring the V600E BRAF mutation compared to dacarbazine.1 In addition to metastatic melanoma, vemurafenib has also been investigated for the treatment of other neoplasms associated with BRAF mutation, including PTC.17 Here we report the case of a patient treated with vemurafenib as investigational therapy for PTC who developed multiple cutaneous keratinocytic proliferations with the majority of the lesions diagnosed as SCCs and AK. The prevailing hypothesis for the development of SCC and/or AK with vemurafenib is that these lesions exhibit paradoxical activation of ERK signaling, which occurs to the greatest extent in the presence of RAS mutations.18 Evidence for this mechanism includes the apparent enrichment for RAS mutations in SCC/KA that arise in vemurafenib-treated patients compared to lesions that arise in non–drug-treated patients.19,20 This case also highlights the association between BRAF inhibition with vemurafenib and the development of cutaneous keratinocytic proliferations. All-trans retinoic acid (ATRA) therapy has been successfully used for chemoprevention of SCCs in several studies.21–23 In a recent trial, Cheepala and colleagues compared the gene expression profiles of control skin to skin exposed to ATRA and concluded that ATRA’s mechanism involves targeting the BRAF signaling pathway.22 This patient’s lesions improved after starting isotretinoin and 5-fluorouracil 5% cream. Furthermore, this combination therapy successfully prevented the
Figure 3. A, Invasion of moderately differentiated squamous cells into the reticular dermis with an enlarged nucleus, prominent nucleoli, and intercellular bridges (inset, asterisk) (hematoxylineosin stain; 3400 original magnification). B, Mitoses (arrows) are present throughout the lesion, including atypical mitoses (inset) (hematoxylin-eosin stain; 3200 original magnification).
Canadian Dermatology Association | Journal of Cutaneous Medicine and Surgery, Vol 17, No 6 (November/December), 2013: pp 419–422
421
Mays et al
development of new AK or SCCs in our patient during a remaining 6 months of treatment with vemurafenib and for an 18-month treatment-free period. Further studies are needed to better understand the association and causality between the development of SCCs and/or AK with vemurafenib therapy. Treatment with ATRA could potentially target the BRAF pathway, thereby enhancing its physiologic differentiation on squamous epithelium. Our clinical results suggest that isotretinoin along with 5-fluorouracil may be successful in the treatment and prevention of SCC and AK in such patients, including for the growing number of patients who will be undergoing therapy with vemurafenib for malignant melanoma. Herein we report a case of vemurafenib therapy associated with the development of AK and SCCs that were successfully treated with isotretinoin and 5-fluorouracil. The combination treatment was effective in preventing further development of lesions for 24 months. Further studies are necessary to elucidate the efficacy of our proposed combination therapy in the prevention of AK and SCC development in other patients receiving vemurafenib therapy. Patients undergoing treatment with vemurafenib should be referred to a dermatologist for close monitoring and further treatment of lesions if they occur.
Acknowledgment Financial disclosure of authors and reviewers: None reported.
References 1. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364:2507–16, doi:10.1056/NEJMoa1103782. 2. Sherman SI. Targeted therapies for thyroid tumors. Mod Pathol 2011;24 Suppl 2:S44–52, doi:10.1038/modpathol.2010.165. 3. Lynch MC, Straub R, Adams DR. Eruptive squamous cell carcinomas with keratoacanthoma-like features in a patient treated with sorafenib. J Drugs Dermatol 2011;10:308–10. 4. Lee WJ, Lee JL, Chang SE, et al. Cutaneous adverse effects in patients treated with the multitargeted kinase inhibitors sorafenib and sunitinib. Br J Dermatol 2009;161:1045–51, doi:10.1111/ j.1365-2133.2009.09290.x. 5. Robert C, Mateus C, Spatz A, et al. Dermatologic symptoms associated with the multikinase inhibitor sorafenib. J Am Acad Dermatol 2009;60:299–305, doi:10.1016/j.jaad.2008.06.034. 6. Hong DS, Reddy SB, Prieto VG, et al. Multiple squamous cell carcinomas of the skin after therapy with sorafenib combined with tipifarnib. Arch Dermatol 2008;144:779–82, doi:10.1001/archderm.144.6.779.
422
7. Garnett MJ, Marais R. BRAF is a human oncogene. Cancer Cell 2004;6:313–9, doi:10.1016/j.ccr.2004.09.022. 8. Sala E, Mologni L, Truffa S, et al. BRAF silencing by short hairpin RNA or chemical blockade by PLX4032 leads to different responses in melanoma and thyroid carcinoma cells. Mol Cancer 2008; 6:751–9. 9. King AJ, Patrick DR, Batorsky RS, et al. Demonstration of a genetic therapeutic index for tumors expressing oncogenic BRAF by the kinase inhibitor SB-590885. Cancer Res 2006;(23):11100–5, doi:10.1158/0008-5472.CAN-06-2554. 10. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature 2002;417:949–54, doi:10.1038/nature00766. 11. Deng G, Bell I, Crawley S, et al. BRAF mutation is frequently present in sporadic colorectal cancer with methylated hMLH1, but not in hereditary nonpolyposis colorectal cancer. Clin Cancer Res 2004;10:191–5, doi:10.1158/1078-0432.CCR-1118-3. 12. Di Nicolantonio F, Martini M, Mollinari F, et al. Wild type BRAF is required for response to panitumumab in metastatic colorectal cancer. J Clin Oncol 2008;26:5668–70, doi:10.1200/JCO.2008.18.0786. 13. Chiosea S, Nijiforova M, Zuo H, et al. A novel complex BRAF mutation detected in solid variant of papillary thyroid carcinoma. Endocr Pathol 2009;20:122–6, doi:10.1007/s12022-009-9073-3. 14. Frasca F, Nucera C, Pellegriti G, et al. BRAF (V600E) mutation and the biology of papillary thyroid cancer. Endocr Relat Cancer 2008; 15:191–205, doi:10.1677/ERC-07-0212. 15. Rajagopalan H, Bardelli A, Lengauer C, et al. Tumorigenesis: RAF/ RAS oncogenes and mismatch-repair status. Nature 2002;418:934, doi:10.1038/418934a. 16. Tsai J, Lee JT, Wang W, et al. Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity. Proc Natl Acad Sci U S A 2008;105:3041–6, doi:10.1073/pnas.0711741105. 17. Flaherty K, Puzanov I, Sosmon J, et al. Phase I study of PLX4032: proof of concept for V600E mutation as therapeutic target in human caner. J Clin Oncol 2009;27:461. 18. Kaplan FM, Mastrangelo MJ, Aplin AE. The wrath of RAFs: rogue behavior of B-RAF kinase inhibitors. J Invest Dermatol 2010;130: 2669–71, doi:10.1038/jid.2010.177. 19. Oberholzer PA, Kee D, Dziunycz P, et al. RAS mutations are associated with the development of cutaneous squamous cell tumors in patients treated with RAF inhibitors. Clin Oncol 2012; 30:316–21, doi:10.1200/JCO.2011.36.7680. 20. Lacouture ME, Chapman PB, Ribas A, et al. Presence of frequent underlying RAS mutations in cutaneous squamous cell carcinomas and keratoacanthomas (cuSCC/KA) that develop in patients during vemurafenib therapy [abstract]. J Clin Oncol 2011;29 Suppl:8520. 21. Fabricius EM, Kruse-Boitschenko U, Schneeweiss U, et al. Model examination of chemoprevention with retinoids in squamous cell carcinomas of the head and neck region and suitable biomarkers for chemoprevention. Int J Oncol 2011 Jul 22. [Epub ahead of print] 22. Cheepala SB, Yin W, Syed Z, et al. Identification of the B-Raf/Mek/ Erk MAP kinase pathway as a target for all-trans retinoid acid during skin cancer promotion. Mol Cancer 2009;8:27, doi:10.1186/ 1476-4598-8-27. 23. Siddikuzzaman, , Guruvayoorappan C, Berlin Grace VM. All trans retinoic acid and cancer. Immunopharmacol Immunotoxicol 2011; 33:241–9, doi:10.3109/08923973.2010.521507.
Canadian Dermatology Association | Journal of Cutaneous Medicine and Surgery, Vol 17, No 6 (November/December), 2013: pp 419–422
Copyright of Journal of Cutaneous Medicine & Surgery is the property of Decker Publishing and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
