PAN-EX: a pooled analysis of two trials of neoadjuvant chemotherapy followed by chemoradiotherapy in MRI-defined, locally advanced rectal cancer

Sclafani, Francesco; Brown, Gina; Cunningham, David; Wotherspoon, Andrew; Tait, Diana; Peckitt, Clare; Evans, Jessica; Yu, Shun; Mendes, Larissa Sena Teixeira; Tabernero, Josep; Glimelius, Bengt; Cervantes, Andrés; Thomas, Janet; Begum, Ruwaida; Oates, J.; Chau, Ian

doi:10.1093/annonc/mdw215

Cited by 65 publications

(70 citation statements)

References 10 publications

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“…Therefore, investigation in a largely homogeneous, prospective cohort of LARC patients is warranted. In this regard, PAN‐EX (a pooled analysis of two academic phase II rectal cancer trials of similar design, EXPERT and EXPERT‐C) provides a unique, valuable platform for exploratory biomarker analyses …”

Section: Discussionmentioning

confidence: 99%

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Analysis of KRAS, NRAS, BRAF, PIK3CA and TP53 mutations in a large prospective series of locally advanced rectal cancer patients

Sclafani

Wilson

Cunningham

et al. 2019

Intl Journal of Cancer

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Little information is available on the clinical significance of cancer‐related genes such as KRAS, NRAS, BRAF, PIK3CA and TP53 in nonmetastatic rectal cancer. We investigated mutations of these genes in a large prospective series of locally advanced rectal cancer (LARC) patients who were recruited into two phase II trials. Mutational analyses were performed with diagnostically validated methods including polymerase chain reaction, capillary electrophoresis single‐strand conformational analysis, Sanger sequencing and next‐generation sequencing. Associations between single or multiple gene mutations and clinicopathological characteristics and treatment outcomes were explored. Of these 269, 210 (78%) patients were assessable. Mutations of KRAS, NRAS, BRAF, PIK3CA and TP53 occurred in 43, 9, 4, 9 and 60% of patients, respectively. Concordance between paired biopsy and resection specimens was 82% for KRAS, 95% for NRAS, 99% for BRAF, 96% for PIK3CA and 63% for TP53. TP53 mutations were associated with extramural venous invasion on baseline MRI (78% vs. 65%, p = 0.04), poor pathological tumour regression (23% vs. 36%, p = 0.05) and a trend toward a worse 5‐year progression‐free survival (PFS; 60% vs. 74%, HR 1.59, p = 0.06). Patients with tumours harbouring mutation of TP53 and either KRAS or NRAS (32%) had a worse 5‐year PFS than those with TP53/KRAS/NRAS wild‐type tumours (54% vs. 72%, HR 1.75, p = 0.02). In univariate analysis, BRAF mutation predicted poor 5‐year overall survival only among patients treated without cetuximab (20% vs. 73%, HR 3.29, p = 0.03). This is one of the largest biomarker studies in a prospective, largely homogeneous, LARC population. Our findings are hypothesis generating and require validation in independent series.

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Section: Discussionmentioning

confidence: 99%

“…PAN‐EX was a pooled analysis of two phase II trials sponsored by The Royal Marsden NHS Foundation Trust . EXPERT was a single‐centre, single‐arm, phase II trial (2001–2005) while EXPERT‐C was an international, multicentre, randomised phase II trial (2005–2008) .…”

Section: Methodsmentioning

confidence: 99%

Analysis of KRAS, NRAS, BRAF, PIK3CA and TP53 mutations in a large prospective series of locally advanced rectal cancer patients

Sclafani

Wilson

Cunningham

et al. 2019

Intl Journal of Cancer

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“…Tumor differentiation, circumferential tumor, mucinous histology and the presence of macroscopic ulceration are associated with poor response to nCRT [20,21,22,23,24]. Imaging modalities including positron emission tomography-computed tomography, magnetic resonance imaging (MRI) and endoscopic ultrasound are currently used for pretreatment staging, assessment of response to nCRT, and restaging after nCRT [25,26,27,28,29,30,31,32]. Findings from these imaging modalities, including tumor regression rates and circumferential resection margin, can potentially predict response to nCRT in rectal cancer [30,31,32,33].…”

Section: Introductionmentioning

confidence: 99%

Predictive and Prognostic Molecular Biomarkers for Response to Neoadjuvant Chemoradiation in Rectal Cancer

Dayde

Tanaka

Jain

et al. 2017

IJMS

138

152

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Abstract:The standard of care in locally advanced rectal cancer is neoadjuvant chemoradiation (nCRT) followed by radical surgery. Response to nCRT varies among patients and pathological complete response is associated with better outcome. However, there is a lack of effective methods to select rectal cancer patients who would or would not have a benefit from nCRT. The utility of clinicopathological and radiological features are limited due to lack of adequate sensitivity and specificity. Molecular biomarkers have the potential to predict response to nCRT at an early time point, but none have currently reached the clinic. Integration of diverse types of biomarkers including clinicopathological and imaging features, identification of mechanistic link to tumor biology, and rigorous validation using samples which represent disease heterogeneity, will allow to develop a sensitive and cost-effective molecular biomarker panel for precision medicine in rectal cancer. Here, we aim to review the recent advance in tissue-and blood-based molecular biomarker research and illustrate their potential in predicting nCRT response in rectal cancer.

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“…The pCR rate was 20.0% among the 240 patients in the EXPERT and EXPERT-C trials who underwent surgery, and T stage and N stage down-staging was observed in 56.6% and 43.4%, respectively 33 . Although both trials lacked a chemoRT-alone control group, these results were thought to represent improvements in treatment response with good long-term disease control in a high-risk population.…”

Section: Systemic Chemotherapy Prior To Chemort and Surgery For Larcmentioning

confidence: 94%

Selective use of radiation for locally advanced rectal cancer: one size does not fit all

Roxburgh

Weiser

2018

Minerva Chir

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INTRODUCTION The last three decades have seen several major advances in the multidisciplinary management of locally advanced rectal cancer (LARC). Although rectal cancer management varies globally, the standard of care for clinical stage II/III rectal cancer in North America remains chemoradiation followed by total mesorectal excision and adjuvant therapy. EVIDENCE ACQUISITION In this review we evaluate the evidence for neoadjuvant therapy in LARC and the variety of treatment options available. EVIDENCE SYNTHESIS We identify heterogeneity of outcomes in stage II/III rectal cancer, leading to the potential for overtreatment. The PROSPECT trial is a multi-centre, international effort to determine whether a selective approach to provision of radiotherapy in stage II/ III LARC is a viable treatment option. Unlike many other studies, the aim of PROSPECT is to reduce treatment rather than increase the intensity of preoperative therapy. CONCLUSION LARC is a heterogeneous disease with varying risk of relapse. Studies are underway to attempt to individualise care to avoid overtreatment while maintaining excellent oncologic outcomes.

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PAN-EX: a pooled analysis of two trials of neoadjuvant chemotherapy followed by chemoradiotherapy in MRI-defined, locally advanced rectal cancer

Cited by 65 publications

References 10 publications

Analysis of KRAS, NRAS, BRAF, PIK3CA and TP53 mutations in a large prospective series of locally advanced rectal cancer patients

Analysis of KRAS, NRAS, BRAF, PIK3CA and TP53 mutations in a large prospective series of locally advanced rectal cancer patients

Predictive and Prognostic Molecular Biomarkers for Response to Neoadjuvant Chemoradiation in Rectal Cancer

Selective use of radiation for locally advanced rectal cancer: one size does not fit all

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