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The Role of EGFR Inhibitors in the Treatment of Metastatic Anal Canal Carcinoma: A Case Series.

ABSTRACT: Anal cancer patients who have exhibited disease progression after having received all approved drugs pose a major therapeutic challenge. In addition to cytotoxic agents, novel targeted agents are being developed and have an established role in the treatment of many solid tumors, including colon cancer. However, their role in anal cancer is yet to be determined. Most anal malignancies are squamous cell carcinomas often strongly expressing epidermal growth factor receptors (EGFRs). Targeting the latter seems to result in favorable changes in tumor growth. We present three cases of refractory anal cancers, treated with EGFR inhibitors, after having received the recommended chemotherapy regimens. We conclude that EGFR inhibitors may play a vital role in the treatment of anal cancer and we suggest that large trials are be conducted in order to clarify their efficacy and to improve therapeutic management.

SUBMITTER: Saif MW

PROVIDER: S-EPMC3136097 | biostudies-other | 2011

REPOSITORIES: biostudies-other

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The Role of EGFR Inhibitors in the Treatment of Metastatic Anal Canal Carcinoma: A Case Series.

Saif Muhammad W MW Kontny Ewa E Syrigos Kostas N KN Shahrokni Armin A

Journal of oncology 20110613

Anal cancer patients who have exhibited disease progression after having received all approved drugs pose a major therapeutic challenge. In addition to cytotoxic agents, novel targeted agents are being developed and have an established role in the treatment of many solid tumors, including colon cancer. However, their role in anal cancer is yet to be determined. Most anal malignancies are squamous cell carcinomas often strongly expressing epidermal growth factor receptors (EGFRs). Targeting the l ...[more]

PMID: 21772841

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Comprehensive Genomic Profiling of Metastatic Squamous Cell Carcinoma of the Anal Canal.

Project description:Squamous cell carcinoma of the anal canal (SCCA) is a rare gastrointestinal malignancy with an increasing annual incidence globally. The majority of cases are linked to prior infection with the human papillomavirus (HPV). For patients with metastatic SCCA, no consensus standard treatment exists. Identification of relevant targeted agents as novel therapeutic approaches for metastatic SCCA has been limited by a lack of comprehensive molecular profiling. We performed whole-exome sequencing on tumor-normal pairs from 24 patients with metastatic SCCA. Tumor tissue from 17 additional patients was analyzed using a 263-gene panel as a validation cohort. Gene expression profiling was performed on available frozen tissue to assess for differential expression patterns. Based on these findings, patient-derived xenograft (PDX) models of SCCA were generated to test targeted therapies against PI3K and EGFR. Despite a low mutation burden, mutations in PIK3CA, MLL2, and MLL3 were among the most commonly mutated genes. An association between TP53 mutations and HPV-negative SCCA tumors was observed. Gene expression analysis suggested distinct tumor subpopulations harboring PIK3CA mutations and for which HPV had integrated into the host genome. In vivo studies demonstrated improvement with anti-EGFR treatment. Gene mutation frequencies, tumor mutation burden, and gene expression patterns for metastatic SCCA appear similar to other HPV-associated malignancies.Implications: This first comprehensive genomic characterization for patients with metastatic SCCA provides further rationale for the integration of SCCA into the development of novel targeted therapies across HPV-related cancers. Mol Cancer Res; 15(11); 1542-50. ©2017 AACR.

| S-EPMC5991496 | biostudies-literature

EGFR and K-ras gene mutation status in squamous cell anal carcinoma: a role for concurrent radiation and EGFR inhibitors?

Project description:BACKGROUND:There is a growing appreciation for radio-sensitiser use in multi-modal cancer treatment models. Squamous cell anal carcinoma (SCAC) is a rare gastrointestinal tumour traditionally treated with concurrent chemotherapy and radiation. Cetuximab, an epidermal growth factor receptor (EGFR) inhibitor, has demonstrated significant efficacy when combined with radiation in squamous cell carcinoma of the head and neck (SccH&N). We wanted to assess EGFR and Kirsten-ras (K-ras) status in SCAC to see whether it compares with SccH&N. METHODS:Over 90 SCAC paraffin-embedded biopsies were mounted onto a tissue microarray and were assessed for EGFR expression by immunohistochemistry. These samples were also assessed for the most frequently mutated K-ras and EGFR exons by high-resolution melting analysis. RESULTS:The EGFR was present in over 90% of samples tested. The K-ras and EGFR mutations were absent in all samples tested, although a synonymous single-nucleotide polymorphism was found in 3 out of 89 samples tested for EGFR exon 19. CONCLUSION:The low rate of K-ras and EGFR mutations, coupled with the high surface expression of EGFR, suggests similarity in the EGFR signalling pathway between SCAC and SccH&N, and thus a potential role for EGFR inhibitors in SCAC. To our knowledge this is the largest cohort of invasive SCAC samples investigated for EGFR and K-ras mutations reported to date.

| S-EPMC3504953 | biostudies-literature

Premalignant lesions of the anal canal and squamous cell carcinoma of the anal canal.

Project description:Squamous cell carcinoma of the anus (SCCA) is a rare tumor. However, its incidence has been increasing in men and women over the past 25 years worldwide. Risk factors associated with this cancer are those behaviors that predispose individuals to human papillomavirus (HPV) infection and immunosuppression. Anal cancer is generally preceded by high-grade anal intraepithelial neoplasia (HGAIN), which is most prevalent in human immunodeficiency virus-positive men who have sex with men. High-risk patients may benefit from screening. The most common presentation is rectal bleeding, which is present in nearly 50% of patients. Twenty percent of patients have no symptoms at the time of presentation. Clinical staging of anal cancer requires a digital rectal exam and a positron emission tomography/computed tomography scan of the chest, abdomen, and pelvis. Endorectal/endoanal ultrasound appears to add more-specific staging information when compared with digital rectal examination alone. Treatment of anal cancer prior to the 1970s involved an abdominoperineal resection. However, the current standard of care for localized anal cancer is concurrent chemoradiation therapy, primarily because of its sphincter-saving and colostomy-sparing potential. Studies have addressed alternative chemoradiation regimens to improve the standard protocol of fluorouracil, misogynic, and radiation, but no alternative regimen has proven superior. Surgery is reserved for those patients with residual disease or recurrence.

| S-EPMC3311505 | biostudies-other

Radiation generates an abscopal response and complete resolution of metastatic squamous cell carcinoma of the anal canal: a case report.

Project description:The abscopal effect is a rare phenomenon in the setting of radiation therapy (RT) for metastatic cancer where tumor regression occurs distant from the site of treatment. A proposed mechanism of the abscopal effect is the activation of a systemic antitumor immune response by localized RT. We report the first case, to our knowledge, of the abscopal effect in squamous carcinoma of the anal canal with metastases to pelvic lymph nodes, liver and bone. After palliative RT to the pelvis with sensitizing chemotherapy, complete response was observed not only in the primary tumor but also in bone and multiple liver metastases at 4 months after treatment, an effect that remained durable at 4-year follow-up. Understanding of the abscopal effect and the immune mechanisms associated with anal cancer may lead to new avenues of research to improve outcome for patients with this rare disease.

| S-EPMC5750188 | biostudies-other

Anal Canal Cancer : subclassification

Project description:Etiologically linked to HPV infection, malignancies of the anal canal have substantially increased in incidence over the last 20 years. Although most anal squamous cell carcinomas (SCC) respond well to chemoradiotherapy, for undetermined reasons, a subgroup of patients experience a poor outcome. Despite cumulative efforts for discovering independent predictors for overall survival, both nodal status and tumor size are still the only reliable factors predicting patient outcome. In the present study, we correlated both proteomic signatures and clinicopathological features of neoplastic lesions arising from two distinct portions of the anal canal: the lower part (squamous zone) and the more proximal anal transitional zone. Although microdissected cancer cells appeared indistinguishable by morphology (squamous phenotype), unsupervised clustering analysis of the whole proteome significantly highlighted the heterogeneity that exists within anal canal tumors. More importantly, two region-specific subtypes of SCC were revealed. The expression profile (sensitivity/specificity) of several selected biomarkers (keratin filaments) further confirmed the subclassification of anal (pre)cancers based on their cellular origin. Less commonly detected compared to their counterparts located in the squamous mucosa, SCC originating in the transitional zone displayed more frequently a poor or basaloid differentiation and were significantly correlated with reduced disease-free and overall survivals. Taken together, we present for the first time direct evidence that anal canal SCC comprises two distinct entities with different cells of origin, proteomic signatures and survival rates. This study forms the basis for a novel dualistic classification of anal carcinoma with implications for management, outcome expectations and possibly therapeutic approaches.

2016-12-20 | PXD004859 | Pride

Changing patterns of anal canal carcinoma in the United States.

Project description:PurposePersistent human papillomavirus infection is associated with squamous cell carcinoma of the anal canal (SCCA). With changing sexual behaviors, SCCA incidence and patient demographics may also have changed in recent years.MethodsThe Surveillance, Epidemiology, and End Results public-use data set from 1973 to 2009 was analyzed to determine incidence trends for and demographic factors characterizing SCCA. Joinpoint analyses identified time points when incidence rates changed. For comparison, similar analyses were conducted for anal adenocarcinoma.ResultsJoinpoint analyses identified 1997 as the single inflection point among 11,231 patients with SCCA, at which the slope of incidence rates statistically increased (1997 to 2009 v 1973 to 1996: risk ratio [RR], 2.2; 95% CI, 2.1 to 2.3). Annual percent change (APC) increased for all SCCA stages and was the greatest for anal carcinoma in situ (CIS; APC, 14.2; 95% CI, 10.2 to 18.4). Demographic changes characterizing later versus earlier time period included younger age at diagnosis and rising incidence rates in all stage, sex, and racial groups. During 1997 to 2009, women were less likely to present with CIS (RR, 0.3; 95% CI, 0.3 to 0.3) but more likely to present with localized (RR, 1.2; 95% CI, 1.1 to 1.3) and regional SCCA (RR, 1.5; 95% CI, 1.4 to 1.7). In contrast, adenocarcinoma APCs among 1,791 patients remained stable during this time period.ConclusionCIS and SCCA incidence increased dramatically after 1997 for men and women, although men were more likely to be diagnosed with CIS. These changes likely resulted from available screening in men and argue for efforts to identify high-risk individuals who may benefit from screening.

| S-EPMC3753461 | biostudies-literature

Molecular characterization of squamous cell carcinoma of the anal canal

Project description:Background Squamous cell carcinoma of the anal canal (SCCA) is an uncommon malignancy with limited therapeutic options. Nivolumab and pembrolizumab show promising results in patients with SCCA. Human papillomavirus (HPV)-negative tumors are frequently TP53-mutated (TP53-MT) and often resistant to therapy. Methods We present a large molecularly-profiled cohort of SCCA, exploring the underlying biology of SCCA, differences between TP53-wild type (TP53-WT) and TP53-MT tumors, and differences between local and metastatic tumors. SCCA specimens (n=311) underwent multiplatform testing with immunohistochemistry (IHC), in situ hybridization (ISH) and next-generation sequencing (NGS). Tumor mutational burden (TMB) was calculated using only somatic nonsynonymous missense mutations. Chi-square testing was used for comparative analyses. Results The most frequently mutated genes included PIK3CA (28.1%), KMT2D (19.5%), FBXW7 (12%), TP53 (12%) and PTEN (10.8%). The expression of PD-1 was seen in 68.8% and PD-L1 in 40.5% of tumors. High TMB was present in 6.7% of specimens. HER2 IHC was positive in 0.9%, amplification by chromogenic in situ hybridization (CISH) was seen 1.3%, and mutations in ERBB2 were present in 1.8% of tumors. The latter mutation has not been previously described in SCCA. When compared with TP53-WT tumors, TP53-MT tumors had higher rates of CDKN2A, EWSR1, JAK1, FGFR1 and BRAF mutations. PD-1 and PD-L1 expression were similar, and high TMB did not correlate with PD-1 (P=0.50) or PD-L1 (P=0.52) expression. Conclusions Molecular profiling differences between TP53-MT and TP53-WT SCCA indicate different carcinogenic pathways which may influence response to therapy. Low frequency mutations in several druggable genes may provide therapeutic opportunities for patients with SCCA.

| S-EPMC8576238 | biostudies-literature

Clinical Benefit from Tyrosine Kinase Inhibitors in Metastatic Merkel Cell Carcinoma: A Case Series of 5 Patients.

Project description:BACKGROUND Merkel cell carcinoma (MCC) is a rare but aggressive neuroendocrine skin cancer. The estimated 5-year survival of patients with metastatic disease is approximately 14%. Cytotoxic chemotherapy is associated with a modest median progression-free survival (PFS) of only 3 months. In recent studies, immunotherapy with anti-PD-1/anti-PD-L1 antibodies has demonstrated a high response rate in immunocompetent patients (>50% in chemotherapy-naïve patients) and responses are typically durable. However, approximately 50% of immunocompetent patients do not respond to immunotherapy. In addition, immunosuppressed patients have limited therapeutic options. Hence, there is a significant unmet need for effective treatments in these subpopulations. CASE REPORT We describe 5 patients (out of 24 total) with metastatic MCC who were treated with a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI), either pazopanib (n=4) or cabozantinib (n=1), with clinical benefit. One patient had a complete response to pazopanib after 3 months of therapy. Four patients had stabilization of disease that lasted from 5 months to 3.5 years. In an immunosuppressed patient with psoriatic arthritis, stabilization of MCC was also associated with improvement in his arthritis that allowed cessation of immunosuppression. Patients did not develop any unusual toxicities from VEGFR-TKIs. CONCLUSIONS Treatment with VEGFR-TKIs demonstrated clinical benefit in this selected small group of patients with metastatic MCC. Prospective investigation of VEGFR-TKIs is warranted in this population, especially in patients with disease refractory to immunotherapy.

| S-EPMC5952731 | biostudies-literature

The role of systemic chemotherapy and multidisciplinary management in improving the overall survival of patients with metastatic squamous cell carcinoma of the anal canal.

Project description:Metastatic squamous cell carcinoma (SCCA) of the anal canal is a rare malignancy for which no standard treatment algorithm exists. To determine the best approach, all patients diagnosed with metastatic SCCA of the anal canal treated at a single institution were evaluated for choice of chemotherapy and treatment outcome. A retrospective study from January 2000 to May 2012 was conducted. Electronic medical records were reviewed for diagnosis of metastatic SCCA of the anal canal. All patients were treatment naïve for metastatic disease and completed all radiographic imaging at our institution. The purpose of this study was to evaluate outcomes among patients who received systemic chemotherapy and if appropriate were referred for multidisciplinary intervention (e.g., surgery, radiofrequency ablation, etc.). Seventy-seven patients fulfilled eligibility criteria. Forty-two patients (55%) received 5-fluorouracil (5-FU) + cisplatin (PF); 24 patients (31%) received carboplatin + paclitaxel (CP); 11 patients (14%) received an alternative regimen. After a median follow-up of 42 months, the median progression-free survival (PFS) for all patients was 7 months; the median overall survival (OS) was 22 months. Thirty-three patients (43%) underwent multidisciplinary management for metastatic disease resulting in a median PFS of 16 months (95% CI: 9.2 -22.8) and median OS of 53 months (95% CI: 28.3 - 77.6). Systemic chemotherapy provides durable survival for patients with surgically unresectable metastatic SCCA of the anal canal. Multidisciplinary management for select patients with metastatic disease effectively improves survival and should be considered whenever possible.

| S-EPMC4294384 | biostudies-other

Metastatic renal cell carcinoma to the sinonasal cavity: a case series.

Project description:Objectives To describe the presentation, work-up, and management of patients with metastatic renal cell carcinoma (RCC) to the sinonasal cavity and skull base, and to describe our current treatment algorithm of endoscopic surgical resection followed by radiation therapy. Design Retrospective review of two recent cases from our institution over a 1-year period, with a relevant review of the literature. Setting A large regional tertiary care facility. Participants Consecutive cases of RCC with metastases to the sinonasal cavity presenting to our institution. Main Outcome Measures Preoperative and postoperative sinonasal outcome test (SNOT)-22 scores, duration of hospital stay, complications, and local disease control Results Patients in this series underwent preoperative embolization followed by endoscopic resection without complication. Postoperatively they were treated with radiation therapy. They experienced improvement in their SNOT-22 scores and are currently free of local disease. Conclusion Metastatic RCC to the sinonasal cavity can be safely treated with preoperative embolization followed by endoscopic surgical resection and radiation therapy, which can result in improvement in sinonasal quality of life and is a potential adjunct for local control of disease.

| S-EPMC3836888 | biostudies-other

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