COMMENTARY

Could Vismodegib Therapy for Basal Cell Carcinoma Increase the Risk for Subsequent Squamous Cell Carcinomas?

Graeme M. Lipper, MD

Disclosures

June 29, 2016

Increased Risk of Cutaneous Squamous Cell Carcinoma After Vismodegib Therapy for Basal Cell Carcinoma

Mohan SV, Chang J, Li S, Henry AS, Wood DJ, Chang AL
JAMA Dermatol. 2016;152:527-532

Vismodegib, a novel smoothened inhibitor (SI) that suppresses tumor growth via inhibition of the sonic hedgehog (Shh) pathway, is approved by the US Food and Drug Administration for the treatment of locally advanced or metastatic basal cell carcinomas (BCCs).[1,2] This orally administered drug is a potent teratogen with side effects including muscle spasms, alopecia, dysgeusia, and fatigue. One long-term concern is that Shh inhibition may inadvertently activate the RAS/MAPK pathway, thereby promoting tumorigenesis.[3] Recent reports have emerged of new-onset keratoacanthomas and cutaneous squamous cell carcinomas (CSCCs) developing in patients with advanced BCCs during vismodegib therapy.[4,5]

Spurred on by these reports, Mohan and colleagues studied the incidence of subsequent non-BCC malignancies in a cohort of 180 patients (68.9% male) with high-risk BCCs (mean age at time of diagnosis, 56 years); 55 of these had been treated with at least 7 days of vismodegib, and 125 were vismodegib-naive.

Investigators controlled for confounding variables including age, sex, immunosuppression, prior radiation or cisplatin treatment, and basal cell nevus syndrome (BCNS) status. Their analysis revealed that:

  1. After accounting for age and BCNS status, vismodegib exposure significantly increased the risk of developing CSCC (hazard ratio, 8.12)

  2. There was no significant increase in other studied cancers (melanomas, gastrointestinal, breast, lung, prostate, hematopoietic, endocrine, or genitourinary).

  3. SCCs in vismodegib-exposed vs naive BCC patients had comparable latency periods, defined as the number of years from BCC diagnosis to diagnosis of the first non-BCC malignancy.

  4. Most CSCCs developed within the first year of vismodegib therapy.

  5. Vismodegib-naive patients were more likely to have in situ CSCC than those taking vismodegib.

Viewpoint

Over the past 5 years, vismodegib has become an important weapon for treating locally advanced or metastatic BCCs, curbing tumor burden in patients with BCNS, inducing regression to debulk BCCs prior to surgical resection, and palliative therapy for inoperable BCCs.[6] This targeted therapy works by suppressing the hyperactive Shh pathway that drives BCC growth. But could this inhibition have the unintended side effect of selecting for tumor cells that have mutated their way around dependence on the Shh pathway?

Mohan and colleagues' case-control study supports this possibility; their cohort of high-risk BCC patients who were treated with vismodegib had an eightfold increased risk of developing subsequent CSCCs. This elevated risk persisted despite controlling for age, BCNS status, and the histologic diagnosis of metatypical BCCs.

In this context, patients with advanced BCCs who are considering vismodegib should be advised that this treatment seems to increase the risk for subsequent SCCs, although there is no evidence to date that these SCCs behave more aggressively or carry a worse prognosis than SCCs arising in vismodegib-naive patients. Whether or not this risk holds true for all patients receiving Shh pathway inhibitors or a specific subset remains to be determined.

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