Jennifer Wang

Treatment for Metastatic Penile Cancer After First-line Chemotherapy Failure: Analysis of Response and Survival Outcomes.

OBJECTIVE To retrospectively estimate the efficacy of various treatments used in men with metastatic penile cancer that progresses after first-line chemotherapy. METHODS Patients were from a 30-patient cohort with stage TxN2-3M0 penile squamous cell carcinoma treated with neoadjuvant paclitaxel, ifosfamide, and cisplatin chemotherapy before planned lymphadenectomy. Nineteen patients (63.3%) had tumor progression or recurrence, and we evaluated the response to subsequent treatment and survival. RESULTS Seventeen had received ≥ 1 salvage therapies; their median survival from first treatment failure was 5.7 months (range, 1.4-30.3 months). Four patients underwent salvage surgery, all of whom experienced further disease progression within 2 months. Four patients received chemoradiotherapy, 1 with stable disease for 13.5 months and 3 with no apparent benefit. Two of 5 evaluable patients (40%) who had received bleomycin, methotrexate, and cisplatin had objective responses (1 complete, 1 partial) but 1 developed fatal pneumonitis. There were no other documented responses to systemic therapy. Median overall survival was 5.6 months for patients who had received a second cisplatin-based treatment at any time and 4.3 months for those who had not (P = .4). CONCLUSION Patients whose metastatic penile carcinoma progresses through or recurs after front-line cisplatin-based chemotherapy experience poor responses to the described salvage treatments, with a median overall survival time of <6 months. Emphasis should be placed on clinical trials for development of effective therapy in this setting.

Intratumoral heterogeneity and chemoresistance in nonseminomatous germ cell tumor of the testis

Background Nonseminomatous germ cell tumor of the testis (NSGCT) is largely curable. However, a small group of patients develop refractory disease. We investigated the hypothesis that intratumoral heterogeneity contributes to the emergence of chemoresistance and the development of refractory tumor subtypes. Results Our institutions records for January 2000 through December 2010 included 275 patients whose primary tumor showed pure embryonal carcinoma (pure E); mixed embryonal carcinoma, yolk sac tumor, and teratoma (EYT); or mixed embryonal carcinoma, yolk sac tumor, seminoma, and teratoma (EYST). Patients with EYST had the highest cancer-specific mortality rate (P = .001). They tended to undergo somatic transformation (P = .0007). Two of 5 patients with clinical stage I EYST who had developed recurrence during active surveillance died of their disease. Materials and Methods In this retrospective study, we evaluated consecutive patients who had been diagnosed with the three most common histological phenotypes of NSGCT. Chemoresistance was defined as the presence of teratoma, viable germ cell tumor, or somatic transformation in the residual tumor or the development of progressive or relapsed disease after chemotherapy. In a separate prospective study, we performed next-generation sequencing on tumor samples from 39 patients to identify any actionable genetic mutations. Conclusions Our data suggest that patients with EYST in their primary tumor may harbor a potentially refractory NSGCT phenotype and are at increased risk of dying from disease. Despite intratumoral heterogeneity, improved patient selection and personalized care of distinct tumor subtypes may optimize the clinical outcome of patients with NSGCT.

Discovery and development of differentially methylated regions in human papillomavirus-related oropharyngeal squamous cell carcinoma: Discovery and development of differentially methylated regions

Human papillomavirus (HPV)‐related oropharyngeal squamous cell carcinoma (OPSCC) exhibits a different composition of epigenetic alterations. In this study, we identified differentially methylated regions (DMRs) with potential utility in screening for HPV‐positive OPSCC. Genome wide DNA methylation was measured using methyl‐CpG binding domain protein‐enriched genome sequencing (MBD‐seq) in 50 HPV‐positive OPSCC tissues and 25 normal tissues. Fifty‐one DMRs were defined with maximal methylation specificity to cancer samples. The Cancer Genome Atlas (TCGA) methylation array data was used to evaluate the performance of the proposed candidates. Supervised hierarchical clustering of 51 DMRs found that HPV‐positive OPSCC had significantly higher DNA methylation levels compared to normal samples, and non‐HPV‐related head and neck squamous cell carcinoma (HNSCC). The methylation levels of all top 20 DNA methylation biomarkers in HPV‐positive OPSCC were significantly higher than those in normal samples. Further confirmation using quantitative methylation specific PCR (QMSP) in an independent set of 24 HPV‐related OPSCCs and 22 controls showed that 16 of the 20 candidates had significant higher methylation levels in HPV‐positive OPSCC samples compared with controls. One candidate, OR6S1, had a sensitivity of 100%, while 17 candidates (KCNA3, EMBP1, CCDC181, DPP4, ITGA4, BEND4, ELMO1, SFMBT2, C1QL3, MIR129–2, NID2, HOXB4, ZNF439, ZNF93, VSTM2B, ZNF137P and ZNF773) had specificities of 100%. The prediction accuracy of the 20 candidates rang from 56.2% to 99.8% by receiver operating characteristic analysis. We have defined 20 highly specific DMRs in HPV‐related OPSCC, which can potentially be applied to molecular‐based detection tests and improve disease management.

TGF-β1 genetic variants predict clinical outcomes of HPV-positive oropharyngeal cancer patients after definitive radiotherapy

Purpose: TGFβ1 plays a critical role in inflammation and immune responses and treatment response and survival. TGFβ1 variants may affect its expression level or functional efficiency, thus modifying tumor status and survival in human papillomavirus (HPV)–positive squamous cell carcinoma of the oropharynx (SCCOP). Experimental Design: We determined tumor HPV16 status and genotyped three TGFβ1 polymorphisms in 564 incident SCCOP patients treated with radiotherapy or chemoradiation. Univariate and multivariable Cox models were used to evaluate the associations between the three polymorphisms and survival. Results: Overall, 85% of patients (482 of 564) had HPV16-positive SCCOP. We found that TGFβ1 rs1982073 had statistically significant associations with survival, whereas TGFβ1 rs1800469 and TGFβ1 rs1800471 did not. Patients with TGFβ1 rs1982073 CT/CC variant genotypes had significantly better overall, disease-specific, and disease-free survival compared with those with the corresponding common homozygous TT genotype (all log-rank: P < 0.001). Furthermore, these genotypes were significantly associated with an approximately 5 times reduced risk of overall death, death owing to disease, and recurrence after multivariable adjustment. Moreover, the stratified analyses by tumor HPV status indicated that the significant effects of TGFβ1 rs1982073 polymorphism on survival were found among HPV16-positive SCCOP patients only. Finally, the functional relevance of these variants was further characterized. Conclusions: Our findings support that the TGFβ1 rs1982073 polymorphism plays a significant role in the prognosis of SCCOP, especially in HPV16-positive SCCOP patients treated with chemoradiation. Prospective studies with larger sample sizes are needed to confirm these findings. Clin Cancer Res; 24(9); 2225–33. ©2018 AACR.