Concurrent BRAFV600E and BRCA mutations in microsatellite stable (MSS) metastatic colorectal cancer (mCRC): Prevalence and case series of mCRC (pts) with prolonged overall survival (OS).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3561-3561
Author(s):  
Timothy Lewis Cannon ◽  
Jamie Randall ◽  
Ethan Sokol ◽  
Sonja Alexander ◽  
Raymond Couric Wadlow ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Homologous Recombination ◽  
Targeted Therapies ◽  
Brca2 Mutation ◽  
Cohort Analysis ◽  
Braf V600e ◽  
Tumor Board ◽  
Brca Mutations ◽  
Molecular Tumor Board

3561 Background: BRAF V600E+, MSS mCRC patients comprise up to 10% of advanced CRC. They have a poor prognosis with median survivals typically <1 year. Despite use of multi-agent first-line chemotherapy regimens and combination targeted therapies, outcomes are still poor. In our Institutional Molecular Tumor Board database, we identified 3 consecutive mCRC pts with MSS/ BRAF V600E who also had a BRCA1 or BRCA2 co-mutation and had prolonged overall survival. Prior studies suggested that BRCA mutations are uncommon in CRC and we queried the Foundation Medicine (FM) genomic database to evaluate the prevalence of these cases as well as those with co-mutations in other homologous recombination genes. Methods: 36,966 CRC pts were sequenced by FMI using hybrid capture comprehensive genomic profiling (CGP) to evaluate all classes of genomic alterations (GA) for pathogenic BRAF mutations and/or a mutation in BRCA1/2 or a co-mutation in other homologous recombination (HR) genes ( BARD1, CDK12, FANCL, PALB2, ATM, RAD54L, CHEK2, BRAF, BRIP1, RAD51D, RAD51C, RAD51B, CHEK1). Selected cohort analysis were BRAF V600E co-mutated with BRCA1 and BRCA2, separated into MSI-H and MSS cohorts. The clinicopathological features and genomic loss of heterozygosity (gLOH) of those with a BRAF V600E and a BRCA1/BRCA2 mutation are described along with 3 consecutive cases of CRC patients, identified through the Inova Schar Cancer Institute (ISCI) molecular tumor board (MTB) registry, whom had prolonged OS. Results: Of 36,966 colorectal cancer pts, 6.6% were BRAF V600E+ and 1.5% had any co-occurring HR gene mutation(s) with 0.6% having co-mutations of BRAF V600E and BRCA1/2. BRCA co-mutations were higher in MSI-High BRAF V600E, however 24.1% of these occurred in MSS BRAF V600E. BRCA1 co-mutated was more commonly associated with MSS BRAF V600E and was associated with a higher gLOH than MSI-H BRAF V600E (18.7% vs 2.8%; p <0.001 ). In our institutional MTB database, (3/241;1.2%) CRC patients were MSS, BRAF V600E+ with BRCA1 or BRCA2 co-mutations, one confirmed germline and 2 somatic in origin, and had average gLOH of 21.4% with overall survivals of 72+(alive), 17+(alive), and 30 months, respectively. Conclusions: Co-existence of BRAF V600E/ BRCA1/2 may represent a unique subset of advanced MSS CRC that may have a better prognosis and represent an opportunity to test novel targeted therapies. Larger prospective clinical validation trials in this subset is warranted.[Table: see text]

Systemic Therapy for Colorectal Cancer

2019 ◽  
Author(s):  
Anna M. Varghese
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Mismatch Repair ◽  
Targeted Therapies ◽  
Growth Factor Receptor ◽  
Braf V600e ◽  
Ongoing Research ◽  
Medical Oncologists ◽  
Epidermal Growth ◽  
Cytotoxic Therapies

Colorectal cancer remains the second most common cause of cancer-related deaths in this country. Although colorectal cancer is best managed by a multidisciplinary team of surgical, radiation, and medical oncologists, cytotoxic therapy remains the backbone of treatment in the metastatic disease setting. In addition to cytotoxic therapies, vascular-targeted therapies and epidermal growth factor receptor (EGFR)–targeted therapies for selected patients with metastatic colorectal cancer improve outcomes for patients with metastatic colorectal cancer. Growing understanding of various biological subsets of colorectal cancer, including BRAF V600E mutant and mismatch repair–deficient colorectal cancers, is expanding treatment opportunities for patients and is the focus of ongoing research. This review contains 4 tables and 57 references. Key Words: chemotherapy, colorectal cancer, fluoropyrimidines, immunotherapy, metastatic, mismatch repair–deficient colorectal cancer, targeted therapy, topoisomerase inhibitors

scholarly journals Personalized Medicine in the Oncology Clinic: Implementation and Outcomes of the Johns Hopkins Molecular Tumor Board

2017 ◽  
pp. 1-19 ◽  
Author(s):  
W. Brian Dalton ◽  
Patrick M. Forde ◽  
Hyunseok Kang ◽  
Roisin M. Connolly ◽  
Vered Stearns ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Targeted Therapy ◽  
Targeted Therapies ◽  
Progression Free Survival ◽  
Molecular Profiling ◽  
Tumor Board ◽  
Free Survival ◽  
Off Label ◽  
Tumor Boards ◽  
Molecular Tumor Board

Purpose Tumor genomic profiling for personalized oncology therapy is being widely applied in clinical practice even as it is being evaluated more formally in clinical trials. Given the complexities of genomic data and its application to clinical use, molecular tumor boards with diverse expertise can provide guidance to oncologists and patients seeking to implement personalized genetically targeted therapy in practice. Methods A multidisciplinary molecular tumor board reviewed tumor molecular profiling reports from consecutive referrals at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins over a 3-year period. The tumor board weighed evidence for actionability of genomic alterations identified by molecular profiling and provided recommendations including US Food and Drug Administration–approved drug therapy, clinical trials of matched targeted therapy, off-label use of such therapy, and additional tumor or germline genetic testing. Results One hundred fifty-five patients were reviewed. Actionable genomic alterations were identified in 132 patients (85%). Off-label therapies were recommended in 37 patients (24%). Eleven patients were treated off-label, and 13 patients were enrolled onto clinical trials of matched targeted therapies. Median progression-free survival of patients treated with matched therapies was 5 months ( 95% CI, 2.9 months to not reached), and the progression-free survival probability at 6 months was 43% (95% CI, 26% to 71%). Lack of locally available clinical trials was the major limitation on clinical actionability of tumor profiling reports. Conclusion The molecular tumor board recommended off-label targeted therapies for a quarter of all patients reviewed. Outcomes were heterogeneous, although 43% of patients receiving genomically matched therapy derived clinical benefit lasting at least 6 months. Until more data become available from precision oncology trials, molecular tumor boards can help guide appropriate use of tumor molecular testing to direct therapy.

What is the benefit for patients suffering from metastatic colorectal cancer (mCRC) after bevacizumab-based regimen (BBR), cetuximab-based regimen (CBR), and panitumumab (P)?

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 595-595
Author(s):  
J. Metges ◽  
J. Ramée ◽  
J. Raoul ◽  
A. Gourlaouen ◽  
M. Porneuf ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Metastatic Colorectal Cancer ◽  
Targeted Therapies ◽  
Primary Tumor ◽  
Progression Free Survival ◽  
Tumor Site ◽  
Primary Tumor Site ◽  
Health Politics ◽  
Private And Public

595 Background: Metastatic colorectal cancer (mCRC) management has been clearly improved by targeted therapies such as anti VEGF and /or anti-HER1 drugs. The evaluation of the use of targeted therapies in the real world is strategic to assess health politics. OMIT Bretagne-Pays de la Loire is a network of private and public cancer centers that has been leading cohort studies evaluating Folfiri-bevacizumab treatment, the cost of targeted therapies and the succession of targeted therapies. Methods: The purpose of this study is to evaluate the benefit and safety of three consecutive targeted therapies in patients with KRAS wild-type unresectable mCRC. Sex, age, localization of the primary tumor site, successive chemotherapeutic regimens, toxicities, response rates, progression free survival and overall survival have been studied. Results: 34 patients (22 men, 12 women, median age 63 years [43-82]) have been prospectively recruited between 2003 and 2010. All of them received bevacizumab specially in association with FOLFIRI, cetuximab in association with irinotecan, panitumumab as monotherapy and others chemotherapies than FOLFOX, FOLFIRI, XELOX. The primary tumor site was colon (71%), junction (5%), and rectum (24%). 22 patients had metastatic colorectal tumor, 28 were operated on their primary tumor and 12 underwent resection after one line of treatment. Patients received successively 3 to 8 different lines of treatment for progressive mCRC. Toxicities of targeted therapies were manageable. Objective responses were observed in 38% (13) of the patients treated with BBR, 37% (11) treated with CBR and 25% (6) treated with P. Disease stabilization was achieved in 32% (11) of the patients treated with BBR, in 10% (3) with CBR and in 8% (2) with P. PFS at 80 months is 15%. Median OS from first metastatic line at death was 47.43 months (24.23-70.84). PFS and OS curves will be shown during the meeting. Conclusions: Our study clearly shows that patients receiving successively the three schedules (BBR, CBR, P) have a high overall survival with manageable side effects. No significant financial relationships to disclose.

Early-onset small bowel and colorectal cancer patients with BRCA mutations: Actionable variants in atypical presentations.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 545-545
Author(s):  
Karen Vikstrom
Keyword(s):  
Colorectal Cancer ◽  
Genetic Testing ◽  
Cancer Patients ◽  
Early Onset ◽  
Brca2 Mutation ◽  
Brca Mutations ◽  
Panel Testing ◽  
Medical Histories ◽  
Atypical Presentations ◽  
Actionable Findings

545 Background: The paradigm of genetic panel testing for hereditary colorectal cancer (CRC) continues to emerge. An association between Hereditary Breast and Ovarian Cancer (HBOC) syndrome and early onset CRC and has been reported, though only significantly associated with BRCA1 mutations. Guidelines do not include CRC in the HBOC spectrum. We describe nine early-onset ( < 55 years) gastrointestinal (GI) cancer patients with germline mutations in BRCA1 or BRCA2 to highlight actionable findings that would have been missed by traditional CRC genetic testing. Methods: The nine affected patients underwent genetic testing using NGS-based multi-gene cancer panels. Genomic DNA variants were identified and classified according to ACMG criteria. Patient medical histories were obtained by referring clinician and documented on test requisition forms, and were de-identified for analysis. Results: Nine patients had a pathogenic (P) variant in BRCA1 (three cases) or BRCA2 (six cases). Four patients were under the age of 32 at the time of their CRC diagnosis. Of the nine cases, only one met NCCN testing criteria for HBOC syndrome. All patients were negative for P variants in the canonical CRC genes (APC, MUTYH, MLH1, MSH2, MSH6, PMS2, EPCAM). Conclusions: In this series, nine unrelated patients with early-onset CRC were found to carry a BRCA1 or BRCA2 mutation. The presence of BRCA mutations in these CRC patients is alone not strong evidence of causation; however, it suggests that clinicians should consider expanded panel testing in the presence of complex family histories, as these patients would have been found negative by traditional genetic tests. As the phenotypic spectrum of classical cancer syndromes is expanded by broad panel-based testing, it is important to identify patients that fall outside traditional diagnostic criteria, as some patients will have actionable findings in unexpected genes.

Visualizing real-world outcomes through the lens of a molecular tumor board: Persona-typing pancreatic cancers for clinical decision support.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e18100-e18100
Author(s):  
Emanuel Petricoin ◽  
Daniel Barg ◽  
Patricia Miren de Arbeloa ◽  
Michael J. Pishvaian ◽  
Edik Matthew Blais
Keyword(s):  
Cell Cycle ◽  
Dna Damage Response ◽  
Real World ◽  
Clinical Decision ◽  
Parp Inhibitors ◽  
Tumor Board ◽  
Brca Mutations ◽  
Pancreatic Cancers ◽  
Damage Response ◽  
Molecular Tumor Board

e18100 Background: Despite the molecular diversity of pancreatic adenocarcinoma, standard therapy options remain largely molecularly-untailored except in the context of DNA damage response alterations such as BRCA mutations, NTRK fusions, or microsatellite instability. Methods: To broaden the utility of molecular profiling, we analyzed real-world outcomes and established 12 molecularly-driven clusters, or “persona types” (PTs), across a cohort of 1280 pancreatic cancers with CLIA-grade genomic/proteomic data (commercially available NGS/IHC panels). Patients were consented into Perthera’s precision oncology platform via referrals from advocacy programs and hospital partnerships for case review by a molecular tumor board (MTB). Persona types were generated using unsupervised k-means clustering of molecularly-tailored therapy recommendations formulated by the MTB. Progression-free survival was documented across all lines of therapy. Results: Personas based on multi-omic profiles and expert-driven recommendations were representative of molecular phenotypes reported in previous studies (e.g. DNA damage response deficiencies, BRAF mutations, other non-KRAS-drivers, SWI/SNF alterations, squamous-associated genes, cell cycle regulators, etc.). To streamline the exploration of real-world outcomes, we developed an interactive dashboard that enables users to compare PFS survival curves across Personas for various therapies such as gemcitabine/nab-paclitaxel, FOLFIRINOX, other standard regimens, immunotherapy, PARP inhibitors, RAF/MEK/ERK inhibitors, and more. Persona types associated with increased/decreased sensitivity to several classes of agents were identified (e.g. PD-1/L1 inhibitors in a persona enriched for cell cycle dysregulation, PARP inhibitors in a persona enriched for BRCA mutations). Conclusions: Empowering oncologists with personalized insights into real-world outcomes may promote investigator-initiated trials and augment clinical decision support, particularly when choosing between standard of care regimens or when exploring potential clinical trial options.

Meat consumption and BRAF mutation status in colorectal cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15135-e15135
Author(s):  
Rosa L. Frias ◽  
Michael Lam ◽  
Michael J. Overman ◽  
Van K. Morris ◽  
David R. Fogelman ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Logistic Regression ◽  
Meat Consumption ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
P Value ◽  
Mutation Status ◽  
Molecular Features ◽  
Total Meat

e15135 Background: Consumption of red and processed meat has been associated with increased risk of developing colorectal cancers, but less is known about the association of meat consumption with tumor molecular features. In this study, we tested the association of total meat consumption with molecular features of colorectal cancer and overall survival in a local cohort of patients. Methods: Data on meat consumption were collected using self-directed environmental surveys from patients with stage IV/locally advanced, treatment refractory colorectal cancer who were enrolled on the Assessment of Targeted Therapies Against Colorectal Cancer clinical protocol. Data on tumor molecular features were collected through medical record review. Patients were categorized into low, medium or high meat consumption groups based on servings per day tertile. Associations between tumor molecular features and meat intake were evaluated by Chi-square and logistic regression. Potential effects of meat consumption on overall survival were assessed using Cox Proportional Hazards models. Analyses were conducted with IBM SPSS v25. Results: Patients consumed an average of 0.74, 1.57 and 3.32 servings of meat per day in the low, medium and high categories, respectively. Out of 593 patients with evaluable data, 27 were found to have a BRAF V600E mutation. Total meat consumption differed significantly by BRAF V600E mutation status (p value 0.02) and by sex (p value < .01), but did not differ by tumor location, microsatellite instability, or RAS mutation status. Using logistic regression, we found that compared to patients with the highest level of meat consumption, those in the medium consumption group may be less likely to have a BRAF V600E mutation (OR 0.24; p value 0.08). Although meat consumption may be associated with BRAF mutation status, it was not predictive of overall survival in our analyses. Conclusions: Among patients in our study, meat consumption may be associated with tumor BRAF V600E mutation status but is not directly associated with survival. Additional work is needed to test this association in cohorts including more BRAF mutant cases. If confirmed, this finding may add further insight into the etiology and biology of these tumors.

Cost-effectiveness of encorafenib plus cetuximab in BRAF V600E-mutated colorectal cancer

2021 ◽  
pp. 107815522110450
Author(s):  
Jacopo Giuliani ◽  
Beatrice Mantoan ◽  
Andrea Bonetti
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Cost Effectiveness ◽  
Metastatic Colorectal Cancer ◽  
Braf V600e ◽  
Line Treatment ◽  
Second Line ◽  
Control Groups ◽  
The Difference ◽  
The Cost

Recently, the introduction of encorafenib in combination with cetuximab was considered as a practice changing in BRAFV600-mutated metastatic colorectal cancer. The aim of this paper was to assess the cost-effectiveness of encorafenib plus cetuximab in the second-line treatment of BRAFV600-mutated metastatic colorectal cancer. BEACON CRC Trail was considered. Incremental cost-effectiveness ratio was calculated as the ratio between the difference of the costs in the intervention and in the control groups (pharmacy costs) and the difference between the effect in the intervention and in the control groups (overall survival). Four hundred forty-one patients were included. Differences in costs between the two arms (encorafenib plus cetuximab vs FOLFIRI plus cetuximab) was 59 501 €, with a cost of 17 500 € per month of overall survival-gain. Combining pharmacological costs of drugs with the measure of efficacy represented by overall survival, at the actual prize encorafenib cannot be considered cost-effectiveness for second-line treatment of BRAFV600-mutated metastatic colorectal cancer.

scholarly journals Tumor Board Participation Among Physicians Caring for Patients With Lung or Colorectal Cancer

2015 ◽  
Vol 11 (3) ◽  
pp. e267-e278 ◽  
Author(s):  
Kenneth L. Kehl ◽  
Mary Beth Landrum ◽  
Katherine L. Kahn ◽  
Stacy W. Gray ◽  
Aileen B. Chen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trial ◽  
Overall Survival ◽  
Stage I ◽  
Tumor Board ◽  
Trial Participation ◽  
Clinical Trial Participation ◽  
Curative Intent

Among patients with lung or colorectal cancer, frequent physician tumor board engagement was associated with patient clinical trial participation and higher rates of curative-intent surgery for stage I to II NSCLC but not with overall survival.

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