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Penile squamous cell carcinoma may benefit from therapies used in HPV-related cancers

Jad Chahoud, MD
Jad Chahoud

SAN FRANCISCO — Characterization of genomic alterations in penile squamous cell carcinoma revealed involvement of multiple cancer genes that likely contribute to tumor development, as well as a genomic profile that appears similar to other HPV-related squamous cell carcinomas, according to study results presented at Genitourinary Cancers Symposium.

This genomic profile may provide a therapeutic rationale for considering strategies successful in other HPV-related cancers, according to the researchers.

“We have a very limited understanding of the molecular alterations in penile squamous cell carcinoma, which has been a limitation to the development novel therapeutic strategies,” Jad Chahoud, MD, fellow in hematology/medical oncology at The University of Texas MD Anderson Cancer Center, told HemOnc Today. “The potential for incorporation of biology into treatment in a rare and fatal cancer was the motivation for characterizing genomic alterations.”

Chahoud and colleagues identified 34 patients (median age, 61; range, 39-83) diagnosed at their institution with penile squamous cell carcinoma who had primary tumors or metastatic lesions sufficient for whole-exome sequencing. Fifty percent of patients had lymphovascular invasion and 50% had perineural invasion.

Twelve of 18 patients (66%) with known HPV status were HPV negative.

The most frequently mutated penile squamous cell carcinoma genes included NOTCH1 (35%), TP53 (35%), CDKN2A (24%), PIK3CA (21%), CASP8 (21%), FAT1 (18%), FBXW7 (15%) and EP300 (12%). All eight of these also are significantly mutated in other squamous cell carcinoma tumor types, according to the researchers.

All eight of these genes are found to be substantial drivers in head and neck squamous cell carcinoma, and five in cervical squamous cell carcinoma. Three genes — CASP8, FXBW7 and EP300 — are only known to be drivers in these tumor types.

“The data identified the top recurrent mutations in penile squamous cell carcinoma, highlighting NOTCH1 mutations in 35% of patients,” Chahoud told HemOnc Today. “Recent evidence emerged that NOTCH1 loss-of-function mutation can be successfully targeted in NOTCH1-mutated head and neck squamous cell carcinoma.

“Also, we showed that the tumor mutation burden in penile squamous cell carcinoma is similar to other squamous tumors where immune checkpoint inhibitors have been approved as part of the systemic therapies available for advanced disease,” he said. “These data could guide future clinical trials in penile squamous cell carcinoma.”

Further, research found that TP53 mutations were more common in HPV-negative penile squamous cell carcinoma, occurring in no patients with HPV-positive disease (P = .03).

EP300 mutations were associated with advanced primary tumor stage, but no mutations were associated with lymph node status.

Overall, these studies suggest that clinical trials for this disease may benefit from insights gained in head and neck cancer and certain other more common squamous sites, Chahoud said.

“We would like to validate these findings in a larger cohort and translate these data to the development of clinical trials in patients with penile squamous cell carcinoma in the frontline and relapsed settings,” he added. – by Alexandra Todak

Reference:

Chahoud J, et al. Abstract 505. Presented at: Genitourinary Cancers Symposium; Feb. 14-16, 2019; San Francisco.

Disclosures: One author reports a consultant/advisory Role with Wolters Kluwer. Chahoud and the other study report no relevant financial disclosures.

Jad Chahoud, MD
Jad Chahoud

SAN FRANCISCO — Characterization of genomic alterations in penile squamous cell carcinoma revealed involvement of multiple cancer genes that likely contribute to tumor development, as well as a genomic profile that appears similar to other HPV-related squamous cell carcinomas, according to study results presented at Genitourinary Cancers Symposium.

This genomic profile may provide a therapeutic rationale for considering strategies successful in other HPV-related cancers, according to the researchers.

“We have a very limited understanding of the molecular alterations in penile squamous cell carcinoma, which has been a limitation to the development novel therapeutic strategies,” Jad Chahoud, MD, fellow in hematology/medical oncology at The University of Texas MD Anderson Cancer Center, told HemOnc Today. “The potential for incorporation of biology into treatment in a rare and fatal cancer was the motivation for characterizing genomic alterations.”

Chahoud and colleagues identified 34 patients (median age, 61; range, 39-83) diagnosed at their institution with penile squamous cell carcinoma who had primary tumors or metastatic lesions sufficient for whole-exome sequencing. Fifty percent of patients had lymphovascular invasion and 50% had perineural invasion.

Twelve of 18 patients (66%) with known HPV status were HPV negative.

The most frequently mutated penile squamous cell carcinoma genes included NOTCH1 (35%), TP53 (35%), CDKN2A (24%), PIK3CA (21%), CASP8 (21%), FAT1 (18%), FBXW7 (15%) and EP300 (12%). All eight of these also are significantly mutated in other squamous cell carcinoma tumor types, according to the researchers.

All eight of these genes are found to be substantial drivers in head and neck squamous cell carcinoma, and five in cervical squamous cell carcinoma. Three genes — CASP8, FXBW7 and EP300 — are only known to be drivers in these tumor types.

“The data identified the top recurrent mutations in penile squamous cell carcinoma, highlighting NOTCH1 mutations in 35% of patients,” Chahoud told HemOnc Today. “Recent evidence emerged that NOTCH1 loss-of-function mutation can be successfully targeted in NOTCH1-mutated head and neck squamous cell carcinoma.

“Also, we showed that the tumor mutation burden in penile squamous cell carcinoma is similar to other squamous tumors where immune checkpoint inhibitors have been approved as part of the systemic therapies available for advanced disease,” he said. “These data could guide future clinical trials in penile squamous cell carcinoma.”

Further, research found that TP53 mutations were more common in HPV-negative penile squamous cell carcinoma, occurring in no patients with HPV-positive disease (P = .03).

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EP300 mutations were associated with advanced primary tumor stage, but no mutations were associated with lymph node status.

Overall, these studies suggest that clinical trials for this disease may benefit from insights gained in head and neck cancer and certain other more common squamous sites, Chahoud said.

“We would like to validate these findings in a larger cohort and translate these data to the development of clinical trials in patients with penile squamous cell carcinoma in the frontline and relapsed settings,” he added. – by Alexandra Todak

Reference:

Chahoud J, et al. Abstract 505. Presented at: Genitourinary Cancers Symposium; Feb. 14-16, 2019; San Francisco.

Disclosures: One author reports a consultant/advisory Role with Wolters Kluwer. Chahoud and the other study report no relevant financial disclosures.

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