Mutational analysis of anal cancers demonstrates frequent PIK3CA mutations associated with poor outcome after salvage abdominoperineal resection

Purpose To evaluate dabrafenib, a selective BRAF inhibitor, combined with trametinib, a selective MEK inhibitor, in patients with BRAF V600–mutant metastatic colorectal cancer (mCRC). Patients and Methods A total of 43 patients with BRAF V600–mutant mCRC were treated with dabrafenib (150 mg twice daily) plus trametinib (2 mg daily), 17 of whom were enrolled onto a pharmacodynamic cohort undergoing mandatory biopsies before and during treatment. Archival tissues were analyzed for microsatellite instability, PTEN status, and 487-gene sequencing. Patient-derived xenografts were established from core biopsy samples. Results Of 43 patients, five (12%) achieved a partial response or better, including one (2%) complete response, with duration of response > 36 months; 24 patients (56%) achieved stable disease as best confirmed response. Ten patients (23%) remained in the study > 6 months. All nine evaluable during-treatment biopsies had reduced levels of phosphorylated ERK relative to pretreatment biopsies (average decrease ± standard deviation, 47% ± 24%). Mutational analysis revealed that the patient achieving a complete response and two of three evaluable patients achieving a partial response had PIK3CA mutations. Neither PTEN loss nor microsatellite instability correlated with efficacy. Responses to dabrafenib plus trametinib were comparable in patient-derived xenograft–bearing mice and the biopsied lesions from each corresponding patient. Conclusion The combination of dabrafenib plus trametinib has activity in a subset of patients with BRAF V600–mutant mCRC. Mitogen-activated protein kinase signaling was inhibited in all patients evaluated, but to a lesser degree than observed in BRAF-mutant melanoma with dabrafenib alone. PIK3CA mutations were identified in responding patients and thus do not preclude response to this regimen. Additional studies targeting the mitogen-activated protein kinase pathway in this disease are warranted.

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Salvage abdominoperineal resection for squamous cell anal cancer: a 30-year single institution experience

European Journal of Surgical Oncology ◽

10.1016/j.ejso.2018.10.187 ◽

2019 ◽

Vol 45 (2) ◽

pp. e46

Author(s):

J. Hagemans ◽

S. Blinde ◽

J. Nuyttens ◽

W. Morshuis ◽

M. Mureau ◽

...

Keyword(s):

Abdominoperineal Resection ◽

Anal Cancer ◽

Squamous Cell ◽

Single Institution ◽

Squamous Cell Anal Cancer ◽

Salvage Abdominoperineal Resection

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Phase II study of cabozantinib (cabo) in patients (pts) with recurrent/metastatic endometrial cancer (EC): A study of the Princess Margaret, Chicago, and California phase II consortia.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.5524 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 5524-5524 ◽

Cited By ~ 1

Author(s):

Neesha C. Dhani ◽

Hal W. Hirte ◽

Julia V. Burnier ◽

Angela Jain ◽

Marcus O. Butler ◽

...

Keyword(s):

Phase Ii ◽

Kinase Inhibitor ◽

Mutational Analysis ◽

Single Agent ◽

Progression Free Survival ◽

Current Data ◽

Pik3ca Mutations ◽

Primary Endpoints ◽

Hand Foot Syndrome ◽

Grade 3

5524 Background: Recurrent/metastatic EC has a poor prognosis with no standard 2ndline therapy. Cabo is a multi-targeted kinase inhibitor of MET, VEGFR, TIE2, AXL & KIT, relevant in epithelial-stromal cross-talk. The role of MET/HGF in aggressive EC biology, where transient benefit of VEGF-targeting is due to MET/HGF, TIE2 & AXL, provides rationale for MET targeting in EC. Methods: PHL86 (NCI#9322/NCT01935934) is a multi-centre, phase II trial of cabo (60mg oral daily dose) in pts with EC recurring within a year of adjuvant chemotherapy (ctx), or with progression after 1 line of ctx for metastatic disease. Experimental (E) cohort was stratified by histology (serous (SER) vs endometroid (END)) in a Simon two-stage design for co-primary endpoints of response rate ( > 30%) & 12-week progression-free-survival (PFS) ( > 55%). Activity was defined as > 7 partial responses (PRs) or > 15 instances of 12 wk-PFS in 36 pts. Pts with rare histology EC were treated in a parallel exploratory (Ex) cohort. Results: From May 2013 to Nov 2016, 102 pts (E: 71; Ex: 31) have been treated with cabo after prior radiation (59) and/or ctx (no. lines: 1(77); 2(22)). Cabo was well tolerated with common toxicities of fatigue, nausea, diarrhea & hand-foot syndrome. Most frequent Grade 3/4 toxicity was hypertension (32/101 pts). Fistula/perforation occurred in 4 of 71 SER/END pts & 4 of 31 Ex pts; no risk factors were identified. In 33 END pts, 6 PRs & 24 instances of > 12-wk PFS were observed; median PFS is 4.8 mths (95% CI: 4.4 – 6.4) with estimated 6-mth PFS of 43% (95% CI: 27 to 59%). In 34 SER pts, 4 PRs & 20 instances of > 12-wk PFS were observed; median PFS is 4.0 mths (95% CI: 2.7 – 4.7) with estimated 6-mth PFS of 30% (95% CI: 15 to 46%). 4 pts have had PFS > 12 mths, 1 SER pt remains on study after 25mths. Mutational analysis demonstrated presence of KRAS with PTEN or PIK3CA mutations in 9 (SER/END) pts, of whom 8/9 pts met 12-wk PFS endpoint, with a median PFS 5.9 mth (4.1 to 15.4). Conclusions: Cabo has single agent activity in END and SER EC with durable disease control. Concurrent mutation in KRAS/PTEN/PIK3CA may enrich for response. The current data support further evaluation of cabo in EC. Clinical trial information: NCT01935934.

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A systematic review of outcomes after salvage abdominoperineal resection for persistent or recurrent anal squamous cell cancer

Colorectal Disease ◽

10.1111/codi.14569 ◽

2019 ◽

Vol 21 (6) ◽

pp. 632-650 ◽

Cited By ~ 4

Author(s):

G. Ko ◽

A. Sarkaria ◽

S. J. Merchant ◽

C. M. Booth ◽

S. V. Patel

Keyword(s):

Systematic Review ◽

Abdominoperineal Resection ◽

Squamous Cell ◽

Squamous Cell Cancer ◽

Cell Cancer ◽

Salvage Abdominoperineal Resection ◽

Anal Squamous Cell Cancer

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Does multiple mutational analysis of the EGFR pathway have a prognostic role in advanced colorectal cancer (CRC)?

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.3612 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 3612-3612

Author(s):

Luisa Foltran ◽

Giuseppe Aprile ◽

Giovanna De Maglio ◽

Federica Edith Pisa ◽

Mariaelena Casagrande ◽

...

Keyword(s):

Braf Mutation ◽

Advanced Colorectal Cancer ◽

Mutational Analysis ◽

Wild Type ◽

Prognostic Role ◽

Braf Mutations ◽

Kras Mutations ◽

Pik3ca Mutations ◽

Negative Prognostic Factor ◽

Impact On Survival

3612 Background: BRAF mutation is widely recognised as a strong negative prognostic factor in advanced CRC, while the prognostic value of KRAS mutations in codons 12-13 remains controversial. Exploring mutations in other downstream components of the EGFR pathway may have an impact on survival. Methods: A consecutive cohort of 201 metastatic CRC patients treated with systemic chemotherapy were analysed for KRAS (12-13-61-146), BRAF, PIK3CA and NRAS genotypes by pyrosequencing on PyroMarkTMQ96 ID instrument (Qiagen, Germany) with commercially available kits Anti-EGFR MoAb response (Diatech Pharmacogenetics, Italy). Accurate microdissection guaranteed more than 70% of cancer cells for each sample. For the purpose of the survival analysis 4 categories were created: (1) KRAS mutated (codons 12-13 only); (2) BRAF mutated; (3) any of KRAS codons 61-146, PIK3CA or NRAS mutations; (4) all-wild type. Log-rank and Cox proportional tests were applied for statistical analysis. Results: KRAS mutations were present in 96 (47.8%) patients: 86 (42.8%) were in codons 12-13. BRAF mutations were found in 11 (5.5%) samples while PIK3CA and NRAS in 33 (16.4%) and 7 (3.5%), respectively. All mutations were mutually exclusive except for 24 (11.9%) patients with concomitant KRAS/PIK3CA mutations. Median survivals for different categories are shown. Patients harbouring BRAF mutation had the worst outcome (p=0.0006). Mutations of any codon of KRAS (12-13-61-146) also negatively impacted on survival (p=0.026), while the all wild-type (KRAS/BRAF/PIK3CA/NRAS) patients had the longest survival (p=0.002). Conclusions: This study suggests the usefulness for early molecular profiling for advanced CRC patients. Mutational analysis of all EGFR pathway components may identify different prognostic subgroups. This information may drive treatment selection in clinical practice and stratification in clinical trials. [Table: see text]

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