Research Article: Biomarkers of basal cell carcinoma resistance to methyl-aminolevulinate photodynamic therapy

Date Published: April 24, 2019

Publisher: Public Library of Science

Author(s): Tamara Gracia-Cazaña, Marta Mascaraque, Silvia Rocío Lucena, Jesús Vera-Álvarez, Salvador González, Ángeles Juarranz, Yolanda Gilaberte, Arianna L. Kim.

http://doi.org/10.1371/journal.pone.0215537

Abstract

Methyl-aminolevulinate photodynamic therapy (MAL-PDT) is an excellent option for the treatment of basal cell carcinoma (BCC). However, up to 25% of cases are resistant to this treatment modality.

The aim of this study was to identify potential biomarkers of BCC response to MAL-PDT.

Clinical, histological, and immunohistochemical (p53, Ki-67, CD-31, COX2, β-catenin, EGFR, and survivin) variables were analyzed in a retrospective study of consecutive BCC patients treated with MAL-PDT at the San Jorge Hospital, Huesca, Spain between January 2006 and December 2015. To deepen on these markers, the effects on p53 and cyclin D1 expression, in vitro response to MAL-PDT of 2 murine BCC cell lines (ASZ and BSZ), was also evaluated.

The retrospective study examined the response to MAL-PDT of 390 BCCs from 182 patients. The overall clinical response rate was 82.8%, with a mean follow-up time of 35.96 months (SD = 23.46). Immunohistochemistry revealed positive p53 in 84.6% of responders but only 15.4% of nonresponsive tumors (p = 0.011). Tumors with increased peripheral palisading of basal cell islands to immunostaining β-catenin responded poorly to PDT (p = 0.01). In line with our findings in patients, in vitro studies revealed a better response to PDT in the p53-positive ASZ cell line than the p53-negative BSZ cell line (p<0.01). Our finding suggest that certain clinicopathological and immunohistochemical variables, particularly p53 expression, may serve as indicators of BCC response to MAL-PDT, and thus facilitate the selection of patients who are most likely to benefit from this therapy.

Partial Text

Methyl-aminolevulinate (MAL) photodynamic therapy (PDT) is an excellent option for the treatment of superficial (sBCC) and nodular (nBCC) basal cell carcinoma (strength of recommendation, A; quality of evidence, 1).[1] The clearance rate after 2 cycles of MAL-PDT is 91% after 3 months of follow-up, decreasing to 76% after 5 years of follow-up.[1] However, despite good response rates, primary or acquired resistance means that some tumors do not respond to treatment.[2]

We retrospectively analyzed the response to MAL-PDT of 390 BCCs from 182 patients. The overall response rate was 82.8%, with a mean follow-up time of 35.96 months (SD = 23.46; range, 3 months to 6 years). In all cases the same light fluency (37 J/cm2) was used. The majority of patients (87.4%) underwent 2 PDT sessions.

In this study we retrospectively evaluated the effects of MAL-PDT on different clinical-pathological and molecular characteristics of BCC. Analysis of clinical variables revealed that the response of nBCCs was poorer than that of sBCCs. Other factors associated with a poorer response were location of the tumor in area H, older age, darker phototype, and a greater number of MAL-PDT sessions. The only histological variable associated with a poor response was the absence of peritumoral lymphocytic inflammatory infiltrate. Finally, we found that negative p53 immunoreactivity and a β-catenin pattern with peripheral reinforcement of islands of basaloid cells were associated with tumor resistance to PDT. These molecular findings were corroborated in vitro by IF and WB in BCC cell lines.

 

Source:

http://doi.org/10.1371/journal.pone.0215537

 

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