A <i>let-7</i> microRNA-Binding Site Polymorphism in <i>KRAS</i> Predicts Improved Outcome in Patients with Metastatic Colorectal Cancer Treated with Salvage Cetuximab/Panitumumab Monotherapy

Saridaki, Zenia; Weidhaas, Joanne B.; Lenz, Heinz‐Josef; Laurent‐Puig, Pierre; Jacobs, Bart; Schutter, Jef De; Roock, Wendy De; Salzman, David W.; Zhang, Wu; Yang, Dongyun; Pilati, Camilla; Bouché, Olivier; Piessevaux, Hubert; Tejpar, Sabine

doi:10.1158/1078-0432.ccr-14-0348

Cited by 57 publications

(48 citation statements)

References 50 publications

(66 reference statements)

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“…3,5 Perhaps most powerful is the extensive evidence that the KRAS-variant is biologically functional, as exemplified by its role as a strong biomarker of response to cancer therapy. KRAS-variant patients with ovarian cancer or head and neck cancer are cisplatin resistant, 5,7 those with colon cancer or head and neck cancer exhibit cetuximab sensitivity, 7,8 and those with non-small cell lung cancer (NSCLC) are resistant to erlotinib but sensitive to sorafenib. 9 Cell line data further supports the unique response of the KRASvariant to chemotherapy exposure.…”

Section: Introductionmentioning

confidence: 99%

“…9 Cell line data further supports the unique response of the KRASvariant to chemotherapy exposure. 8 Women with the KRAS-variant are also at a significantly increased risk of developing multiple primary cancers, including breast and ovarian cancer, as well as a third independent cancer in their lifetime. 6 Multiple primary cancer, although difficult to predict, is not rare, as one in 8 cancer patients will be diagnosed with a new primary cancer after their first cancer diagnosis (metachronous cancer), and one in 40 patients will be diagnosed with 2 cancers at the same time (synchronous cancer).…”

Section: Introductionmentioning

confidence: 99%

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Estrogen withdrawal, increased breast cancer risk and the KRAS-variant

et al. 2015

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Keywords: breast cancer risk, estrogen withdrawal, KRAS-variant, multiple primary breast cancer, triple negative breast cancer, tumor biologyThe KRAS-variant is a biologically functional, microRNA binding site variant, which predicts increased cancer risk especially for women. Because external exposures, such as chemotherapy, differentially impact the effect of this mutation, we evaluated the association of estrogen exposures, breast cancer (BC) risk and tumor biology in women with the KRAS-variant. Women with BC (n D 1712), the subset with the KRAS-variant (n D 286) and KRAS-variant unaffected controls (n D 80) were evaluated, and hormonal exposures, KRAS-variant status, and pathology were compared. The impact of estrogen withdrawal on transformation of isogenic normal breast cell lines with or without the KRAS-variant was studied. Finally, the association and presentation characteristics of the KRAS-variant and multiple primary breast cancer (MPBC) were evaluated. KRAS-variant BC patients were more likely to have ovarian removal pre-BC diagnosis than non-variant BC patients (p D 0.033). In addition, KRAS-variant BC patients also appeared to have a lower estrogen state than KRAS-variant unaffected controls, with a lower BMI (P < 0.001). Finally, hormone replacement therapy (HRT) discontinuation in KRAS-variant patients was associated with a diagnosis of triple negative BC (P < 0.001). Biologically confirming our clinical findings, acute estrogen withdrawal led to oncogenic transformation in KRAS-variant positive isogenic cell lines. Finally, KRAS-variant BC patients had greater than an 11-fold increased risk of presenting with MPBC compared to non-variant patients (45.39% vs 6.78%,.87], P < 0.001). Thus, estrogen withdrawal and a low estrogen state appear to increase BC risk and to predict aggressive tumor biology in women with the KRAS-variant, who are also significantly more likely to present with multiple primary breast cancer.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Estrogen withdrawal, increased breast cancer risk and the KRAS-variant

et al. 2015

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“…Interestingly, this finding An association between LCS-6 G allele and better prognosis was also reported in a series of stage III-IV CRC patients enriched with KRAS mutation [15]. Finally, in a recent analysis of the NCCTG N0147 trial, the outcome of G carriers with KRAS mutant stage III colon cancer appeared to be more similar to that of patients with KRAS wild-type tumours than that of patients with LCS-6 TT genotype and KRAS mutant tumour [16]. Altogether, these data seem to indicate that the LCS-6 variant may mitigate the unfavourable prognosis associated with KRAS mutation in the non-metastatic setting [17,18].…”

Section: Discussionmentioning

confidence: 53%

“…To our knowledge, this is the first report on the role of the LCS-6 variant in a homogeneous series of LARC. Previous studies investigating this SNP were either restricted to patients with colon cancer or conducted in unselected CRC populations [7,[9][10][11][12][13][14][15][16]. However, differences exist between colon and rectal cancers with regards to tumour biology and treatment approach including frequency of microsatellite instability and BRAF mutation, prognostic relevance of KRAS mutation, miRNA expression profile and routine use of radiotherapy in LARC [21].…”

Section: Discussionmentioning

confidence: 99%

“…A number of studies investigated the role of the LCS-6 variant either as a prognostic marker in early CRC or as a predictive marker for anti-epidermal growth factor receptor (EGFR) therapies in metastatic CRC [7,[9][10][11][12][13][14][15][16]. The results have been largely inconsistent possibly due to a significant inter-study heterogeneity with regard to sample size, patient characteristics and treatment.…”

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2188 Prognostic role of the LCS-6 KRAS variant in locally advanced rectal cancer: Results of the EXPERT-C trial

Sclafani¹,

Chau²,

Cunningham³

et al. 2015

European Journal of Cancer

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Background: Lethal-7 (let-7) is a tumour suppressor miRNA which acts by down-regulating several oncogenes including KRAS. A single-nucleotide polymorphism (rs61764370, T > G base substitution) in the let-7 complementary site 6 (LCS-6) of KRAS mRNA has been shown to predict prognosis in early-stage colorectal cancer (CRC) and benefit from anti-epidermal growth factor receptor monoclonal antibodies in metastatic CRC. Patients and methods:We analysed rs61764370 in EXPERT-C, a randomised phase II trial of neoadjuvant CAPOX followed by chemoradiotherapy, surgery and adjuvant CAPOX plus or minus cetuximab in locally advanced rectal cancer. DNA was isolated from formalin-fixed paraffin-embedded tumour tissue and genotyped using a PCR-based commercially available assay. Kaplan-Meier method and Cox regression analysis were used to calculate survival estimates and compare treatment arms.Results: A total of 155/164 (94.5%) patients were successfully analysed, of whom 123 (79.4%) and 32 (20.6%) had the LCS-6 TT and LCS-6 TG genotype, respectively. Carriers of the G allele were found to have a statistically significantly higher rate of complete response (CR) after neoadjuvant therapy (28.1% versus 10.6%; P = 0.020) and a trend for better 5-year progression-free survival (PFS) [77.4% versus 64.5%: hazard ratio (HR) 0.56; P = 0.152] and overall survival (OS) rates (80.3% versus 71.9%: HR 0.59; P = 0.234). Both CR and survival outcomes were independent of the use of cetuximab. The negative prognostic effect associated with KRAS mutation appeared to be stronger in patients with the LCS-6 TT genotype (HR PFS 1.70, P = 0.078; HR OS 1.79, P = 0.082) compared with those with the LCS-6 TG genotype (HR PFS 1.33, P = 0.713; HR OS 1.01, P = 0.995). Conclusion:This analysis suggests that rs61764370 may be a biomarker of response to neoadjuvant treatment and an indicator of favourable outcome in locally advanced rectal cancer possibly by mitigating the poor prognosis of KRAS mutation. In this setting, however, this polymorphism does not appear to predict cetuximab benefit.

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The KRAS-Variant and Cetuximab Response in Head and Neck Squamous Cell Cancer

et al. 2017

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Importance There is a significant need to find biomarkers of response to radiation and cetuximab in locally advanced head and neck squamous cell carcinoma (HNSCC), as well as biomarkers predicting altered immunity, thereby enabling personalized treatment. Objective To evaluate if the KRAS-variant, a germ-line mutation in a microRNA-binding site in KRAS, is a predictive biomarker of cetuximab response and altered immunity in the setting of radiation and cisplatin treatment. To evaluate the interaction of the KRAS-variant with p16 status and blood-based TGF-β1. Design Advanced HNSCC patients from NRG Oncology RTOG 0522, a Phase III trial of cisplatin plus radiation+/−cetuximab, were included in this study, and patients with available samples were genotyped for the KRAS-variant. Methods Genomic DNA was tested for the KRAS-variant in a CLIA-certified laboratory. Correlation between the KRAS-variant, p16 positivity, outcome, and TGF-β1 levels was evaluated. Hazard ratios (HR) were estimated by Cox model. Main Outcomes and Measures The correlation of KRAS-variant status with cetuximab response and outcome, p16 status, and plasma TGF-β1 levels was tested. Results Of 891 RTOG 0522 patients eligible for protocol analyses, 413 had biological samples for KRAS-variant testing, and 376 had plasma for TGF-β1 measurement. Seventy patients (16.9%) had the KRAS-variant. Overall, for KRAS-variant patients, cetuximab improved both progression-free survival (PFS) for the first year (HR 0.31, 95%CI 0.10–0.94, p=0.04) and overall survival (OS) in years 1–2 (HR 0.19, 95%CI 0.04–0.86, p=0.03). There was a significant interaction of the KRAS-variant with p16 status for PFS in patients treated without cetuximab (p=0.04). In p16 positive patients, KRAS-variant patients treated without cetuximab had worse PFS than non-variant patients (HR 2.59, 95%CI 0.91–7.33, p=0.07). There was a significant three-way interaction between the KRAS-variant, p16 status and treatment for OS (p=0.02). KRAS-variant patients had significantly elevated TGF-β1 plasma levels (p=0.03), and a trend for worse treatment-related toxicity. Conclusion and Relevance KRAS-variant HNSCC patients significantly benefit from the addition of cetuximab to radiation and cisplatin, and there is a significant interaction between the KRAS-variant and p16 status. Elevated TGF-β1in KRAS-variant patients suggests that cetuximab may help these patients by overcoming TGF-beta induced suppression of antitumor immunity.

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A let-7 microRNA-Binding Site Polymorphism in KRAS Predicts Improved Outcome in Patients with Metastatic Colorectal Cancer Treated with Salvage Cetuximab/Panitumumab Monotherapy

Cited by 57 publications

References 50 publications

Estrogen withdrawal, increased breast cancer risk and the KRAS-variant

Estrogen withdrawal, increased breast cancer risk and the KRAS-variant

2188 Prognostic role of the LCS-6 KRAS variant in locally advanced rectal cancer: Results of the EXPERT-C trial

The KRAS-Variant and Cetuximab Response in Head and Neck Squamous Cell Cancer

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