Vismodegib Linked To Second Malignancy Risk After BCC

Patients who use vismodegib for advanced basal cell carcinoma may be at increased risk of a developing a second cancer, driven by an elevated rate of cutaneous squamous cell carcinoma

medwireNews: Patients treated with the smoothened inhibitor vismodegib for advanced basal cell carcinoma (BCC) may have an increased risk of developing a second malignancy, most commonly cutaneous squamous cell carcinoma (CSCC), preliminary research suggests.

The findings “warrant close follow-up by dermato-oncologists of patients during and after treatment with vismodegib”, say the authors of an editorial accompanying the article in JAMA Dermatology.

Martin Leverkus, from Rheinisch-Westfälische Technische Hochschule Aachen in Germany, and commentators emphasise: “As the benefit of vismodegib is substantial for most patients who lack alternatives for the treatment of advanced BCC, we need to be aware that the therapeutic success potentially comes at a neoplastic price.”

The case–control study followed up 180 patients who were diagnosed with BCC between 1998 and 2014, 55 of whom were treated with the smoothened inhibitor. Patients given vismodegib were significantly younger at BCC diagnosis than controls (mean, 52 vs 59 years) and more likely to be diagnosed with basal cell nevus syndrome (BCNS; 23.6 vs 0.8%).

Patients who received vismodegib were followed up for a median of 8.5 years, during which time 29.1% of patients developed a non-BCC malignancy after a median of 6.6 years; controls were followed up for 5.5 years and 40.0% were diagnosed with a secondary tumour after a median of 2.3 years.

Patients who received vismodegib were a significant 6.37 times more likely to develop a non-BCC malignancy than unexposed individuals, after adjusting for a raft of potential confounding factors, and this hazard ratio (HR) remained a significant 5.02 when assessing only the 166 patients without BCNS.

As expected, increasing age at BCC diagnosis was also a significant risk factor for development of secondary malignancy, with a HR of 1.04 for all patients and when assessing patients without BCNS, report Anne Lynn Chang, from Stanford University School of Medicine in Redwood City, California, USA, and co-investigators.

CSCC was the most common non-BCC malignancy, accounting for 75% of the 16 patients given vismodegib who developed a secondary tumour and 66.0% of the 50 affected controls. This was followed by melanoma (18.8 and 18.0%, respectively), and gastrointestinal malignancy (6.3 and 2.0%).

And after adjusting for age and BCNS, patients who used vismodegib were a significant 8.12 times more likely than controls to develop CSCC, although there was not a significantly increased risk of any other tumour type. The risk of secondary malignancy was still elevated in vismodegib users after accounting for patients with metatypical or basosquamous index BCC, which was significantly more common in cases than controls.

“We speculate that the high mutational load of the epidermis (compared with other organs) from UV radiation and other insults may lead to its being ‘spring-loaded’ to produce CSCC once the hedgehog pathway is inhibited by vismodegib”, the authors write.

Until prospective clinical trials can confirm the findings, they suggest that “careful surveillance through regular total-body skin checks by a dermatologist may be prudent, particularly in older adults”, recommending such checkups for at least a year as this was the main period for CSCC detection.


Mohan SV, Chang J, Shufeng L, et al. Increased risk of cutaneous squamous cell carcinoma after vismodegib therapy for basal cell carcinoma. JAMA Dermatol 2016; Advance online publication 24 February. doi:10.1001/jamadermatol.2015.4330

Rübben A, Hilgers R-D, Leverkus M. Hedgehog blockade for basal cell carcinoma. Coming at a (secondary neoplastic) price. JAMA Dermatol 2016; Advance online publication 24 February.doi:10.1001/jamadermatol.2015.5239.

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