KRAS genotyping in rectal adenocarcinoma specimens with low tumor cellularity after neoadjuvant treatment

Boissière‐Michot, Florence; Lopez-Crapez, Evelyne; Frugier, Hélène; Berthe, Marie-Laurence; Ho-Pun-Cheung, Alexandre; Assenat, Éric; Maudelondé, Thierry; Lamy, Pierre‐Jean; Bibeau, Frédéric

doi:10.1038/modpathol.2011.210

Cited by 31 publications

(21 citation statements)

References 48 publications

(55 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Spatial and temporal intratumour molecular heterogeneity is a landmark of many malignancies including colorectal cancer . Studies addressing this phenomenon in nonmetastatic rectal cancer are limited and results not always consistent . By analysing a relatively large number of paired tumour tissues from pretreatment biopsies and posttreatment resection samples, we found a high concordance (≥95%) for NRAS , BRAF and PIK3CA while the concordance for KRAS and TP53 was lower at 82 and 63%, respectively.…”

Section: Discussionmentioning

confidence: 77%

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

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 77%

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

View full text Add to dashboard Cite

show abstract

“…Our subgroups of pre- and post-CRT on which mutational analysis was performed were small ( n = 26 and n = 21, respectively); however, we did not see any significant difference in the mutation rates between these groups. Other investigators have shown that fewer mutations are detected in post-CRT specimens, due to the paucity of cellular material after CRT [18]. However, it is likely that mutational profiles are similar between pre- and post-CRT specimens as has been demonstrated by others where it has been shown that there is a high concordance of mutations in KRAS , NRAS , BRAF , and PIK3CA between pre- and post-FOLFOX treated colorectal cancers, and as was shown in this study [19].…”

Section: Discussionmentioning

confidence: 99%

Mutational and Clinical Predictors of Pathologic Complete Response in the Treatment of Locally Advanced Rectal Cancer

Russo

Ryan

Borger

et al. 2013

J Gastrointest Canc

View full text Add to dashboard Cite

Purpose Preoperative chemoradiation (CRT) for locally advanced rectal adenocarcinoma achieves pathologic complete response (pCR) in 8–20 % of patients. Mutations in critical cancer genes may contribute to lack of pCR. We retrospectively evaluated our institutional experience to determine potential mutational and clinical predictors of pCR in patients treated with CRT. Methods Patients with locally advanced rectal adenocarcinoma treated with preoperative CRT (n = 79) were identified. A clinical cancer genotyping assay evaluated 140 hotspot mutation sites across 15 cancer genes in 47 patients with sufficient tissue. Mutational profiles were compared in pre- and post-CRT specimens and with pCR rate. Clinical variables were evaluated using logistic regression. Results Genotyping identified mutations in KRAS (43 %), APC (17 %), BRAF (4 %), NRAS (4 %), PIK3CA (4 %), and TP53 (11 %). In the entire cohort, 21.5 % had a pCR. No patients with BRAF, NRAS, APC, or TP53 achieved a pCR. pCR rate was 23.5 % (4/17) in wild-type tumors versus 3.3 % (1/30) in those with a mutation. There was no difference in the mutation rates in pre- versus post-CRT specimens. On univariate analysis, clinical predictors of pCR included post-RT carcinoembriogenic antigen level of ≤2.5 and smaller tumor size. No patients with a pCR developed recurrence. Conclusion Patients without mutations in commonly mutated cancer genes may be associated with a higher likelihood of having a pCR after preoperative CRT. This should be confirmed in a prospective study.

show abstract

“…Although chemotherapy or radiotherapy do not alter the genetic status of cancer cells,42 KRAS genotyping on post-treatment samples is challenged by the paucity of neoplastic cells 43. In these circumstances, highly sensitive assays coupled with laser capture microdissection that selects a pure population of tumour cells while avoiding contamination from surrounding tissue reduce the possibility of missing a mutation in the KRAS gene.…”

Section: The Samplementioning

confidence: 99%

KRAS testing in metastatic colorectal carcinoma: challenges, controversies, breakthroughs and beyond

et al. 2013

View full text Add to dashboard Cite

Metastatic colorectal cancer harbouring a mutation in codon 12 or 13 of the KRAS gene does not benefit from therapy with antibodies targeting the epidermal growth factor receptor (EGFR). The implementation of community KRAS testing is generating a rapid flow of new data that have implications for the pathologist and testing guidelines besides the physician. Therefore, it seems timely to draw together the threads of this large body of information in order that pathologists can be knowledgeable partners in the multidisciplinary process of targeted cancer therapy and to help refine current testing guidelines. This review addresses (1) the most relevant methodological and technical aspects of KRAS testing in terms of sample site (primary/metastatic), test specimens (resection/biopsy/cytology) and the diverse molecular methods available; (2) the issues related to daily practice, namely, the timing of the test, its turnaround time and the quality control procedures; and (3) the evidence related to the relationship between KRAS genetic intratumoural heterogeneity, clinical sensitivity of mutational detection tools and anti-EGFR treatment outcome. Hopefully, in the near future, elucidation of the potential of biomarker panels and of the mechanisms underlying primary and acquired resistance to anti-EGFR therapy will refine even further personalised treatment regimens for patients with metastatic colorectal cancer.

show abstract

KRAS genotyping in rectal adenocarcinoma specimens with low tumor cellularity after neoadjuvant treatment

Cited by 31 publications

References 48 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

Mutational and Clinical Predictors of Pathologic Complete Response in the Treatment of Locally Advanced Rectal Cancer

KRAS testing in metastatic colorectal carcinoma: challenges, controversies, breakthroughs and beyond

Contact Info

Product

Resources

About