scholarly journals BRAF mutant colorectal cancer: ErbB2 expression levels as predictive factor for the response to combined BRAFi/ErbB1 inhibitors

2020 ◽  
Author(s):  
Evelina Miele ◽  
Luana Abballe ◽  
Gian Paolo Spinelli ◽  
Zein Mersini Besharat ◽  
Giuseppina Catanzaro ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Single Agent ◽  
Braf V600e ◽  
Oncogenic Signaling ◽  
Expression Levels ◽  
Combination Strategies ◽  
Erbb2 Expression ◽  
Set Up ◽  
Molecular Phenotypes ◽  
Braf Mutant

Abstract Background: Colorectal cancer (CRC) is a heterogeneous disease with a complex biology and has a wide number of altered genes such as BRAF, KRAS and PIK3CA. Advances with new-targeted therapies have been achieved and available treating options have prolonged patient’s survival. However, BRAF-mutated CRC patients remain unresponsive to available therapies with RAF inhibitors (RAFi) alone or combined with ErbB inhibitors (ErbBi). These unmet needs require further exploitation of oncogenic signaling in order to set up individualized treatments. Methods: To this end, we tested the efficacy of single agent or combined treatments using the BRAFi, vemurafenib and two different ErbBi: panitumumab and afatinib in CRC cells characterized by different molecular phenotypes. Results: Combination strategies with BRAFi and ErbBi achieved a better response in BRAF V600E mutated cells expressing high levels of ErbB2. Conclusions: In conclusion our findings allow us to indicate that high ErbB2 expression levels is a positive predictor factor since those patients are responsive to BRAFi/ErbBi combination.

scholarly journals BRAF mutant colorectal cancer: ErbB2 expression levels as predictive factor for the response to combined BRAFi/ErbB1 inhibitors

2019 ◽  
Author(s):  
Evelina Miele ◽  
Luana Abballe ◽  
Gian Paolo Spinelli ◽  
Besharat Zein Mersini ◽  
Giuseppina Catanzaro ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Single Agent ◽  
Braf V600e ◽  
Oncogenic Signaling ◽  
Expression Levels ◽  
Combination Strategies ◽  
Erbb2 Expression ◽  
Set Up ◽  
Molecular Phenotypes ◽  
Braf Mutant

Abstract Background: Colorectal cancer (CRC) is a heterogeneous disease with a complex biology and has a wide number of altered genes such as BRAF, KRAS and PIK3CA. Advances with new-targeted therapies have been achieved and available treating options have prolonged patient’s survival. However, BRAF-mutated CRC patients remain unresponsive to available therapies with RAF inhibitors (RAFi) alone or combined with ErbB inhibitors (ErbBi). These unmet needs require further exploitation of oncogenic signaling in order to set up individualized treatments. Methods: To this end, we tested the efficacy of single agent or combined treatments using the BRAFi, vemurafenib and two different ErbBi: panitumumab and afatinib in CRC cells characterized by different molecular phenotypes. Results: Combination strategies with BRAFi and ErbBi achieved a better response in BRAF V600E mutated cells expressing high levels of ErbB2. Conclusions: In conclusion our findings allow us to indicate that high ErbB2 expression levels is a positive predictor factor since those patients are responsive to BRAFi/ErbBi combination.

scholarly journals BRAF mutant colorectal cancer: ErbB2 expression levels as predictive factor for the response to combined BRAFi/ErbB1 inhibitors

2019 ◽  
Author(s):  
Evelina Miele ◽  
Luana Abballe ◽  
Gian Paolo Spinelli ◽  
Zein Mersini Besharat ◽  
Giuseppina Catanzaro ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Single Agent ◽  
Braf V600e ◽  
Oncogenic Signaling ◽  
Expression Levels ◽  
Combination Strategies ◽  
Erbb2 Expression ◽  
Set Up ◽  
Molecular Phenotypes ◽  
Braf Mutant

Abstract Background: Colorectal cancer (CRC) is a heterogeneous disease with a complex biology and has a wide number of altered genes such as BRAF, KRAS and PIK3CA. Advances with new-targeted therapies have been achieved and available treating options have prolonged patient’s survival. However, BRAF-mutated CRC patients remain unresponsive to available therapies with RAF inhibitors (RAFi) alone or combined with ErbB inhibitors (ErbBi). These unmet needs require further exploitation of oncogenic signaling in order to set up individualized treatments. Methods: To this end, we tested the efficacy of single agent or combined treatments using the BRAFi, vemurafenib and two different ErbBi: panitumumab and afatinib in CRC cells characterized by different molecular phenotypes. Results: Combination strategies with BRAFi and ErbBi achieved a better response in BRAF V600E mutated cells expressing high levels of ErbB2. Conclusions: In conclusion our findings allow us to indicate that high ErbB2 expression levels is a positive predictor factor since those patients are responsive to BRAFi/ErbBi combination.

scholarly journals BRAF mutant colorectal cancer: ErbB2 expression levels as predictive factor for the response to combined BRAFi/ErbB1 inhibitors

2020 ◽  
Author(s):  
Evelina Miele ◽  
Luana Abballe ◽  
Gian Paolo Spinelli ◽  
Zein Mersini Besharat ◽  
Giuseppina Catanzaro ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Unmet Needs ◽  
Single Agent ◽  
Braf V600e ◽  
Oncogenic Signaling ◽  
Combination Strategies ◽  
Erbb2 Expression ◽  
Set Up ◽  
Molecular Phenotypes ◽  
Braf Mutant

Abstract Background: Colorectal cancer (CRC) is a heterogeneous disease with a complex biology and a wide number of altered genes such as BRAF, KRAS and PIK3CA. Advances with new-targeted therapies have been achieved and available treating options have prolonged patient’s survival. However, BRAF-mutated CRC patients remain unresponsive to available therapies with RAF inhibitors (RAFi) alone or combined with ErbB inhibitors (ErbBi). These unmet needs require further exploitation of oncogenic signaling in order to set up individualized treatments. Methods: To this end, we tested the efficacy of single agent or combined treatments using the BRAFi, vemurafenib and two different ErbBi: panitumumab and afatinib in CRC cells characterized by different molecular phenotypes. Results: Combination strategies with BRAFi and ErbBi achieved a better response in BRAF V600E mutated cells expressing high levels of ErbB2. Conclusions: Our findings support the importance of ErbB2 evaluation in BRAF-mutated CRC patients and its role as a positive predictor factor of response to BRAFi/ErbBi combination.

scholarly journals BRAF mutant colorectal cancer: ErbB2 expression levels as predictive factor for the response to combined BRAF/ErbB inhibitors

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Evelina Miele ◽  
Luana Abballe ◽  
Gian Paolo Spinelli ◽  
Zein Mersini Besharat ◽  
Giuseppina Catanzaro ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Predictive Factor ◽  
Expression Levels ◽  
Erbb2 Expression ◽  
Braf Mutant

Outcomes of BRAF mutant metastatic melanoma (MM) patients (pts) after cessation of targeted therapy (TT) with BRAF or BRAF/MEK inhibitor(i).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9564-9564
Author(s):  
Natalie Jackson ◽  
Theresa Rodgers ◽  
Ida John ◽  
Denai R. Milton ◽  
Lauren Elaine Haydu ◽  
...  
Keyword(s):  
Single Agent ◽  
Complete Response ◽  
Braf V600e ◽  
Response To Treatment ◽  
Cancer Center ◽  
Full Cohort ◽  
Time To Recurrence ◽  
Braf Mutant ◽  
Unacceptable Toxicity

9564 Background: Since their introduction into the clinic a decade ago, BRAF and BRAF/MEKi have dramatically changed the outcomes of pts with BRAF mutant MM. While typically, these agents are administered until progression (PD), other reasons for stopping TT include unacceptable toxicity, complete response to treatment, or pt/physician decision or preference. The outcomes for MM pts that stop TT for reasons other than PD are largely unknown. Here we report the clinical features and outcomes of the largest cohort of MM pts who stopped TT for reasons other than PD to date. Methods: Under an institutionally approved database, we identified MM pts treated at the MD Anderson Cancer Center with BRAF±MEK inhibitors, and their records were reviewed to identify pts that stopped TT for reasons other than PD. Pts demographics, treatment information and clinical outcomes were recorded. Overall survival (OS) time was computed from three start dates (initial diagnosis, initial unresectable stage III melanoma, 1st dose of TT) to last known vital sign. Pts alive at the last follow-up date were censored. Time to recurrence was computed from date of 1st dose of TT to recurrence. Pts who did not experience disease recurrence were censored The Kaplan-Meier method was used to estimate OS and time to recurrence. Results: A total of 58 pts were identified, 32 (55%) were male. Most pts had a BRAF V600E (n = 49) or V600K (n = 6) mutation. At TT initiation median age was 59.5 years (range 29- 95), LDH was within normal range in 46 (85%), median number of prior systemic therapies was 1 (range 0-5), with 50% of pts receiving prior systemic therapy. Most (n = 33; 57%) pts were treated with single agent BRAFi (12 with dabrafenib, 11 vemurafenib). Among pts treated with combination TT (n = 25), most received dabrafenib with trametinib (n = 21; 84%). Median TT treatment duration was 9.5 months (range 0.03-80.5 months). Reasons for TT discontinuation were unacceptable toxicity (n = 29; 50%) and pt or physician decision/preference in responding patients (n = 23; 40%). At time of TT discontinuation, 48% of pts had achieved a complete response (CR), 28% a partial response (PR), and 22% stable disease (SD), 1 patient had unknown disease status. With standard follow-up, after stopping TT, 40 pts (69%) have recurred or experienced PD, with a median time to recurrence of 14.9 months (95% CI:7.8-26.3 months). At PD, 32 (76%) of pts had new metastatic sites. After PD 26 pts (63%) pts received BRAF/MEKi, 11 (44%) achieved a CR and 6 (24%) a PR, and 5 (20%) for a response rate of 88%; while 3 (12%) pt had PD as best response and 1 was unknown. For the full cohort, the median OS from time of 1st dose of TT was 6.4 years. Conclusions: Among MM pts who stopped TT for reasons other than PD, the majority of pts recurred, but most responded to re-introduction of TT. This information can help to inform discussion with pts regarding cessation of, or re-challenge with, TT.

Molecular determinants of capecitabine efficacy in colorectal cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3606-3606
Author(s):  
D. Vallbohmer ◽  
H. Kuramochi ◽  
D. Shimizu ◽  
K. D. Danenberg ◽  
J. N. Nielsen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Clinical Outcome ◽  
Single Agent ◽  
Progression Free Survival ◽  
First Line ◽  
Free Survival ◽  
Expression Levels ◽  
Cox 2 ◽  
Gene Expression Levels

3606 Background: Capecitabine offers physicians a more convenient treatment for advanced colorectal cancer (CRC), with manageable toxicity and antitumor activity comparable to that of continuous-infusion therapies with 5-fluorouracil (5-FU). However, there are no validated and established predictive factors for clinical outcome of capecitabine efficacy in CRC. Therefore we investigated whether intratumoral mRNA expression levels of genes involved in the capecitabine/5-FU metabolism (cytidine deaminase (CDA), dihydropyrimidine dehydrogenase (DPD), folylpolyglutamate synthase (FPGS), gamma-glutamyl hydrolase (GGH), thymidine phosphorylase (TP), thymidylate synthase (TS)) and in angiogenesis (cyclooxygenase 2 (Cox-2), epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF)) are associated with the clinical outcome of patients with metastatic CRC treated with first-line capecitabine. Methods: Thirty-seven patients with metastatic CRC were enrolled in this study and treated with single agent capecitabine.The intratumoral mRNA levels of CDA, COX-2, DPD, EGFR, FPGS; GGH, TP, TS, and VEGF were assessed from paraffin-embedded tissue samples using laser-capture-microdissection methods and quantitative real-time PCR. Results: There were20 women and 17 men with a median age of 61 years (range 49–74). The median progression-free survival was 6.7 months (95% CI, 4.8–11.6 months), with a median follow up of 14.4 months (range: 1.3 to 18.7 months). Complete response was observed in 1 (3%), partial response in 6 (20%), stable disease in 14 (47%) and progressive disease in 9 (30%) patients (response was inevaluable in 7 patients). Higher gene expression levels of DPD were associated with resistance to capecitabine (P= 0.032; Kruskal-Wallis test). Patients with a lower mRNA amount of DPD (≤0.46) had a longer progression-free survival compared with patients that had a higher mRNA amount (8.0 vs. 3.3 months; adjusted P=0.048; log-rank test). Conclusions: This pilot study suggests that intratumoral gene expression levels of DPD may be useful to predict the clinical outcome of patients with metastatic CRC with first-line single agent capecitabine treatment. Our data are hypothesis generating and should be validated in larger and prospective clinical trials. [Table: see text]

Prognostic value of RAS, BRAF, and PIK3CA mutations in early-stage colorectal cancer.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 594-594
Author(s):  
Jennifer Elizabeth Byer ◽  
Nishi Kothari ◽  
TzuHua Juan ◽  
Jamie K. Teer ◽  
Michael J. Schell ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Survival Data ◽  
Braf Mutation ◽  
Prognostic Value ◽  
Early Stage ◽  
Stage I ◽  
Braf V600e ◽  
Pik3ca Mutations ◽  
1000 Genomes ◽  
Braf Mutant

594 Background: Activating mutations in the KRAS, BRAF and PIK3CA oncogenes deregulate growth-factor pathways and promote metastasis in colorectal cancer (CRC). The prognostic value of these mutations has been reported with conflicting results in early CRC. We evaluated RAS, BRAF, and PIK3CA mutations as prognostic biomarkers in early stage (stage I-III) colorectal cancer (CRC) patients. Methods: Tumor samples collected from 302 early stage CRC patients diagnosed between 1998 and 2010 were analyzed as part of a multi-institutional observational study. Targeted exome sequencing was performed using the Illumina NGS platform with 50-100X coverage of mutations. The BWA/GATK pipeline was used to identify variants and indels. Matched normal samples were not available for comparison to identify somatic mutations, therefore 1000 Genomes was used to filter normal variants. Variants identified in 1000 Genomes with an MAF <0.01 were filtered. Overall survival data was collected via retrospective chart review. Extended RAS, BRAF V600E, and PIK3CA (exon 9 and 20) mutations were evaluated. The log-rank test was used to compare survival distributions. Results: 302 patients were eligible for analysis (53 stage I, 125 stage II, 124 stage III). 109 patients had RAS mutations (KRAS or NRAS), 41 patients had BRAF mutations, and 29 patients had PIK3CA mutations. Of the 247 patients with microsatellite stability (MSS) 98 were RAS mutant, 10 were BRAF mutant, and 19 were PIK3CA mutant. Of the 55 patients with microsatellite instability high (MSI-H) 11 were RAS mutant, 31 were BRAF mutant, and 10 were PIK3CA mutant. BRAF mutation was prognostic for decreased OS (p= 0.0245), particularly in patients with MSS tumors (p=0.0141). RAS and PIK3CA mutations did not have prognostic value for OS (p =0.72 and 0.23 respectively). Conclusions: In early stage colorectal cancer, we confirmed BRAF mutation is prognostic for OS particularly in MSS patients. RAS and PIK3CA mutations did not confer prognostic value.

Pilot study of vemurafenib and panitumumab combination therapy in patients with BRAF V600E mutated metastatic colorectal cancer.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 611-611 ◽  
Author(s):  
Rona D. Yaeger ◽  
Andrea Cercek ◽  
Eileen Mary O'Reilly ◽  
Diane Lauren Reidy ◽  
Nancy E. Kemeny ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Stable Disease ◽  
Tumor Regression ◽  
Performance Status ◽  
Pilot Trial ◽  
Braf V600e ◽  
Egfr Inhibition ◽  
Correlative Studies ◽  
Braf Mutant

611 Background: BRAF mutant metastatic colorectal cancer (mCRC) is an aggressive subset of colorectal cancer that exhibits minimal response to selective RAF inhibitors. Preclinical data suggest that epidermal growth factor receptor (EGFR) reactivation with RAF inhibition attenuates the efficacy of RAF inhibitors in mCRC and that combined EGFR and RAF inhibition may be a promising therapeutic strategy. Methods: We undertook a pilot trial to assess the response rate and safety of the combination of the selective RAF inhibitior vemurafenib and anti-EGFR antibody panitumumab in patients with BRAF mutant mCRC. Patients received panitumumab 6 mg/kg IV every 14 days starting on day 1 and vemurafenib 960 mg orally twice daily continuously starting on day 8, with treatment staggered for planned correlative studies. Results: Fifteen patients received treatment. Median age was 62 years (range 22-83 years), seven patients (47%) were male, and 11 patients (73%) had a right-sided primary tumor. Performance status was ECOG 0 in four patients (27%) and ECOG 1 in 11 patients (73%). All patients had progressed through at least one standard treatment regimen, and eight patients (53%) had received previous fluoropyrimidine, oxaliplatin, and irinotecan chemotherapy. Acneiform rash (all grade 1 or 2) (53%), fatigue (53%), and arthralgias (40%) were the most frequently observed treatment-related adverse events. Treatment response was assessed in 12 patients because two patients died from disease progression before the first scan and one patient withdrew consent soon after starting treatment. Two patients (13%) had confirmed partial responses (100% and 64% regression) lasting 40 and 24 weeks, respectively. Eight patients (53%) had stable disease (SD) with tumor regression of >15% by RECIST measurement in six of these patients, including two of whom achieved stable disease lasting over six months. Conclusions: Combined RAF and EGFR inhibition is well tolerated and leads to tumor regression in a subset of patients with BRAF mutant mCRC. Planned correlative studies will evaluate degree of pathway inhibition and reactivation of other upsteam pathways with vemurafenib and panitumumab treatment. Clinical trial information: NCT01791309.

BRAF-V600E and microsatellite instability prediction through CA-19-9/CEA ratio in patients with colorectal cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15065-e15065
Author(s):  
Pashtoon Murtaza Kasi ◽  
Saivaishnavi Kamatham ◽  
Dorin Colibaseanu ◽  
Faisal Shahjehan ◽  
Amit Merchea
Keyword(s):  
Colorectal Cancer ◽  
Microsatellite Instability ◽  
Tumor Markers ◽  
Treatment Options ◽  
Braf V600e ◽  
P Value ◽  
Repair Deficiency ◽  
Compare And Contrast ◽  
Braf Mutant ◽  
Antigen Tumor

e15065 Background: Colorectal cancer (CRC) is a heterogeneous disease. Specifically for patients with BRAF-V600E mutations and/or mismatch repair deficiency or microsatellite instability-high (dMMR/MSI-High), there have been significant advances in terms of treatment options. Early identification of these subsets of patients has both prognostic and predictive value. We wanted to highlight an observation of utilizing 2 simple, rapid and universally available lab tests i.e. carbohydrate cancer antigen 19-9 and carcinoembryonic antigen tumor markers, the ratio (CA-19-9/CEA) of which can distinctly identify these patients. Methods: We included and analyzed the ratio of CA-19-9/CEA levels in patients with metastatic CRC at Mayo Clinic from December 2016 to February 2019, where both the results were available. Non-parametric tests were done to compare and contrast the differences in the median ratio and tumor marker levels. Results: BRAF-V600E mutant CRC patients had a discordantly profound elevation in CA-19-9 levels as opposed to the CEA levels. The median CA-19-9/CEA ratio was 20 (range: 0.3-167.3) in BRAF-V600E MSS patients as opposed to 4.40 (range: 0.003-216.2) in all other patients, p-value of 0.007 (Table). Similarly, the mean CA-19-9/CEA ratio for BRAF V600E MSS tumors was 57.15 (S.D.± 62.76) versus 10.5 (S.D.± 33.90) for all other types. Furthermore, this discordant elevation is not seen in BRAF-mutant MSI-High or any MSI-High patients (median CA-19-9/CEA ratio - 0.46). Conclusions: To date, this is the first report utilizing the ratio of tumor markers CA-19-9/CEA as predictive rather than just prognostic markers. It clearly identifies BRAF-V600E MSS and the MSI-High CRC patients from other subsets.[Table: see text]

Clinicopathologic features and impact of metastasectomy in patients with BRAF-mutant metastatic colorectal cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15547-e15547
Author(s):  
Jianwei Zhang ◽  
Cailu Shen ◽  
Jianxia Li ◽  
Zehua Wu ◽  
Huabin Hu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Metastatic Colorectal Cancer ◽  
Systemic Treatment ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Clinicopathologic Features ◽  
Significant Difference ◽  
The Impact ◽  
Braf Mutant

e15547 Background: BRAF V600E mutation is associated with poor prognosis in patients with metastatic colorectal cancer (mCRC), while the non-V600E mutation mCRC patients showed better prognosis than that of V600E mutation. The clinicopathologic features between V600E and non-V600E mutation has not yet been fully evaluated. And the impact of metastasectomy for patients with BRAF-mutant mCRC was not well-known. Methods: A retrospective study was conducted to evaluate the clinical and pathological characteristics of patients with BRAF-mutant mCRC. Next generation sequencing (22-gene panel) was performed in some of the patients. Survival was also analyzed in the cohort of BRAF V600E and non-V600E mutation with or without metastasectomy. Results: Between December 2014 and August 2020, 116 patients with BRAF-mutant mCRC were enrolled, including 94 patients with BRAF V600E mutation and 22 patients with non-V600E mutation. Significant difference was observed in the prevalence of peritoneal metastasis (69.1% vs. 27.3%, P = 0.001) and lung metastasis (11.7% vs. 36.4%, P = 0.009) between BRAF V600E mutation and non-V600E mutations. In genomic profile, SMAD4 mutation (30.7% vs. 13.7%) showed higher prevalence in patients with BRAF V600E mutation than that of non-V600E mutations, while RAS mutation (18.2% vs. 6.4%) and FBXW7 mutation (13.7% vs 3.1%) had higher incidence in BRAF non-V600E mutations than that of V600E mutation. Patients with BRAF V600E mutation showed a poorer overall survival than those with non-V600E mutations (13.9 vs. 26.8 months, P = 0.038). Totally, 46 patients received metastasectomy after systemic treatment. The median survival for BRAF V600E patients with or without metastasectomy was not reach (42.3+ months) vs. 8.3 months, respectively ( P < 0.001), and for non-V600E patients with or without metastasectomy was not reach (64.2+ months) vs. 23.3 months, respectively (P < 0.001). In multivariate analysis, ECOG performance status (0-1 vs. 2) ( P = 0.001), Staging (IVa-b vs. IVc) ( P = 0.01) and metastasectomy ( P = 0.001) were independent prognostic factors of overall survival. Conclusions: BRAF V600E mutation defines a subgroup of mCRC with worse prognosis. Metastasectomy might improve the survival benefit in carefully selected BRAF-mutant mCRC patients after systemic treatment.

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