Comprehensive genomic profiling of anal squamous cell carcinoma reveals distinct genomically defined classes

Chung, Jon; Sanford, Eric M.; Johnson, Adrienne; Klempner, Samuel J.; Schrock, Alexa B.; Palma, Norma Alonzo; Erlich, Rachel; Frampton, Garrett M.; Chalmers, Zachary R.; Vergilio, Jo‐Anne; Rubinson, Douglas A.; Sun, Jiayi; Chmielecki, Juliann; Yelensky, Roman; Suh, James; Lipson, Doron; George, Thomas J.; Elvin, Julia A.; Stephens, Philip J.; Miller, Vincent A.; Ross, Jeffrey S.; Ali, Siraj M.

doi:10.1093/annonc/mdw152

Cited by 82 publications

(90 citation statements)

References 29 publications

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“…In the combined (pilot plus extension) cohort, 10 of 31 tumors (32%) harbored a PIK3CA mutation, similar to the rate reported in recent targeted sequencing studies. [11, 12] Similarly, the overall mutation frequency of FBXW7 in the pooled cohort (6/31, 19%) is comparable to the rate described in other HPV-associated SCCs. [12]…”

Section: Resultssupporting

confidence: 55%

“…[10] Targeted sequencing of known cancer genes has revealed mutations in EGFR , KRAS , and PIK3CA , and a recent study using a combination of targeted sequencing and immunohistochemistry (IHC) revealed high levels of EGFR expression and frequent mutations in the PIK3CA/AKT pathway. [11-13] However, no exome-wide mutational studies are available and the impact of CRT on genomic evolution is unknown.…”

Section: Introductionmentioning

confidence: 99%

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Genomic Evolution after Chemoradiotherapy in Anal Squamous Cell Carcinoma

Mouw

Cleary

Reardon

et al. 2017

Clinical Cancer Research

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Purpose Squamous cell carcinoma of the anal canal (ASCC) accounts for 2-4% of gastrointestinal (GI) malignancies in the US and is increasing in incidence; however, genomic features of ASCC are incompletely characterized. Primary treatment of ASCC involves concurrent chemotherapy and radiation (CRT), but the mutational landscape of resistance to CRT is unknown. Here, we aim to compare mutational features of ASCC in the pre- and post-CRT setting. Experimental Design We perform whole exome sequencing of primary (n=31) and recurrent (n=30) ASCCs and correlate findings with clinical data. We compare genomic features of matched pre- and post-CRT tumors to identify genomic features of CRT response. Finally, we investigate the mutational underpinnings of an extraordinary ASCC response to immunotherapy. Results We find that both primary and recurrent ASCC tumors harbor mutations in genes such as PIK3CA and FBXW7 that are also mutated in other HPV-associated cancers. Overall mutational burden was not significantly different in pre- versus post-CRT tumors, and several examples of shared clonal driver mutations were identified. In two cases, clonally related pre- and post-CRT tumors harbored distinct oncogenic driver mutations in the same cancer gene (KRAS or FBXW7). A patient with recurrent disease achieved an exceptional response to anti-Programmed Death (PD-1) therapy, and genomic dissection revealed high mutational burden and predicted neoantigen load. Conclusion We perform comprehensive mutational analysis of ASCC and characterize mutational features associated with CRT. Although many primary and recurrent tumors share driver events, we identify several unique examples of clonal evolution in response to treatment.

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Section: Resultssupporting

confidence: 55%

Section: Introductionmentioning

confidence: 99%

Genomic Evolution after Chemoradiotherapy in Anal Squamous Cell Carcinoma

Mouw

Cleary

Reardon

et al. 2017

Clinical Cancer Research

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“…The most commonly mutated gene was PIK3CA (33% samples) with TP53 second most frequent in 15%. Further evidence of the high frequency of these mutations comes from data (using a 236 gene NGS panel) from 70 anal cancers (Chung et al , 2016). In total, 87% were HPV positive.…”

Section: Molecular Mechanisms For Differential Sensitivity To Crt Inmentioning

confidence: 99%

Biomarkers in anal cancer: from biological understanding to stratified treatment

et al. 2016

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Squamous cell carcinomas of the anus and anal canal represent a model of a cancer and perhaps the first where level 1 evidence supported primary chemoradiotherapy (CRT) in treating locoregional disease with curative intent. The majority of tumours are associated with infection with oncogenic subtypes of human papilloma virus and this plays a significant role in their sensitivity to treatment. However, not all tumours are cured with CRT and there remain opportunities to improve outcomes in terms of oncological control and also reducing late toxicities. Understanding the biology of ASCC promises to allow a more personalised approach to treatment, with the development and validation of a range of biomarkers and associated techniques that are the focus of this review.

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“…Specifically in anal cancer, there is evidence that EGFR is overexpressed, and is independent of gene amplification (11). Moreover, KRAS and BRAF mutations appear rare in these tumors, supporting a role for EGFR inhibitor therapies, since these therapies have not shown benefit in patients with mutant tumors (12–18). These observations suggest that the addition of EGFR inhibition to CRT has potential for clinical benefit for patients with anal cancer.…”

Section: Introductionmentioning

confidence: 99%

“…These observations suggest that the addition of EGFR inhibition to CRT has potential for clinical benefit for patients with anal cancer. There is evidence of clinical benefit in treating metastatic anal cancer patients with cetuximab alone or in combination with irinotecan, even in patients who are heavily pre-treated (18). Unfortunately, recent clinical trials using cetuximab have shown significant toxicity when combined with conventional CRT for patients with anal cancer (19,20).…”

Section: Introductionmentioning

confidence: 99%

Significance of Co-expression of Epidermal Growth Factor Receptor and Ki67 on Clinical Outcome in Patients With Anal Cancer Treated With Chemoradiotherapy: An Analysis of NRG Oncology RTOG 9811

Doll

Moughan

Klimowicz

et al. 2017

International Journal of Radiation Oncology*Biology*Physics

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Purpose To measure co-expression of EGFR and Ki67 proteins in pre-treatment tumor biopsies of anal cancer patients enrolled on NRG Oncology RTOG 9811, a phase III trial comparing 5FU/MMC/RT (Arm A) vs. 5FU/cisplatin/RT (Arm B), and to correlate expression with clinical outcome. Materials/Methods EGFR and Ki67 co-expression was measured after constructing a tissue microarray using fluorescence immunohistochemistry and automated quantitative image analysis (AQUA). Ki67 score within EGFR high vs. low areas (Ki67ratio in EGFRhigh:low) in each tumor core was analyzed at the median, quartiles and as a continuous variable. Associations between the tumor markers and clinical endpoints [overall and disease-free survival (OS, DFS), locoregional and colostomy failure (LRF, CF), and distant metastases (DM] were explored. Results 282 pre-treatment tumors were analyzed from NRG Oncology RTOG 9811. Of evaluated specimens, 183 (65%, n=89, Arm A; n=94, Arm B) were eligible and analyzable. There were no significant differences in baseline characteristics or outcomes between analyzable and unanalyzable patient cases. Median follow-up was 6.0 years. On multivariate analysis, after adjusting for gender, patients with Ki67ratio in EGFRhigh:low ≥ median had worse OS (HR=2.41, 95% C.I. = [1.38, 4.19], p=0.0019). After adjusting for N stage and largest tumor dimension, patients with Ki67ratio in EGFRhigh:low ≥ median had a higher risk of a disease-free failure (HR=1.85, 95% C.I. = [1.18, 2.92], p=0.0078). Technical validation with an independent anal cancer patient cohort was performed and shows a very similar biomarker score distribution. Conclusions High Ki67ratio in EGFRhigh:low is associated with worse clinical outcome in this subset of patients with anal cancer treated with chemoradiation on NRG Oncology RTOG 9811. Evaluation within a clinical trial will be required to determine whether patients with these tumor characteristics may specifically benefit from an EGFR targeted therapeutic agent.

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Comprehensive genomic profiling of anal squamous cell carcinoma reveals distinct genomically defined classes

Abstract: This is the first comprehensive genomic analysis of ASCC, and the results suggest new therapeutic approaches. Differing genomic profiles between HPV-associated and HPV-negative ASCC warrants further investigation and may require novel therapeutic and preventive strategies.

Cited by 82 publications

References 29 publications

Genomic Evolution after Chemoradiotherapy in Anal Squamous Cell Carcinoma

Genomic Evolution after Chemoradiotherapy in Anal Squamous Cell Carcinoma

Biomarkers in anal cancer: from biological understanding to stratified treatment

Significance of Co-expression of Epidermal Growth Factor Receptor and Ki67 on Clinical Outcome in Patients With Anal Cancer Treated With Chemoradiotherapy: An Analysis of NRG Oncology RTOG 9811

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