Κλινικοπαθολογοανατομικές διαφορές και συσχετίσεις μεταξύ καρκίνου του δεξιού και αριστερού τμήματος του παχέος εντέρου

Υπάρχουσα γνώση: Οι διαφορές σε ιστοπαθολογικό και μοριακό επίπεδο μεταξύ καρκίνου του δεξιού και του αριστερού τμήματος του παχέος εντέρου αναφέρθηκαν πρώτη φορά στη βιβλιογραφία από τον Bufill το 1990. Έκτοτε μεγάλος αριθμός μελετών έχει επιβεβαιώσει τις διαφορές μεταξύ τους σε επιδημιολογικό επίπεδο, σε επίπεδο κλινικής εμφάνισης, συννοσηροτήτων και βιολογικής συμπεριφοράς, τα οποία θα μπορούσαν να σχετίζονται με τις διαφορές στην πρόγνωση και την ολική επιβίωση μεταξύ τους. Στόχος: Σκοπός της παρούσης εργασίας είναι να διερευνήσει στατιστικά σημαντικές διαφορές μεταξύ Ελλήνων ασθενών με καρκίνο του δεξιού και αριστερού τμήματος του παχέος εντέρου αναφορικά με επιδημιολογικά, κλινικά, ιστοπαθολογικά και μοριακά δεδομένα, λαμβάνοντας υπόψη την ανταπόκριση των ασθενών σε στοχευμένες θεραπείες και υπολογίζοντας τυχόν διαφορές σε περιόδους προόδου νόσου ελεύθερης επιβίωσης στην πρώτη και δεύτερη γραμμή θεραπείας αλλά και στην ολική επιβίωση μεταξύ τους. Υλικό και μέθοδος: Η παρούσα μελέτη παρατήρησης περιέλαβε 144 ασθενείς με ιστολογικά επιβεβαιωμένο καρκίνο παχέος εντέρου ανεξαρτήτως σταδίου που έλαβαν χημειοθεραπευτική αγωγή σε ελληνικό ογκολογικό νοσοκομείο για χρονικό διάστημα 2.5 ετών. Οι κλινικές πληροφορίες, οι συννοσηρότητες, τα ιστολογικά και μοριακά χαρακτηριστικά συλλέχτηκαν αναδρομικά από τους φακέλους των ασθενών, ενώ τα χορηγηθέντα χημειοθεραπευτικά σχήματα, οι στοχευτικοί παράγοντες, οι χρονικές περίοδοι προόδου νόσου ελεύθερης επιβίωσης στην πρώτη και δεύτερη γραμμή θεραπείας και η ολική επιβίωση καταγράφηκαν αναδρομικά και προοπτικά. Η στατιστική ανάλυση έγινε με το στατιστικό πακέτο SPSS. Αποτελέσματα: 86 άνδρες και 58 γυναίκες συμμετείχαν στην μελέτη. 100 (69.4%) ασθενείς με εντόπιση της πρωτοπαθούς εστίας στο αριστερό κόλον και 44 (30.6%) στο δεξιό κόλον. Ασθενείς με δεξιά εντόπιση εμφάνισαν σε μεγαλύτερο ποσοστό αναιμία (OR=3.09), ενώ οι ασθενείς με αριστερή εντόπιση εμφάνισαν σε μεγαλύτερο ποσοστό αίμα στις κενώσεις (OR=3.37) και αίσθημα ατελούς κένωσης (OR=2.78). Αναφορικά με τα συνοδά νοσήματα οι ασθενείς με καρκίνο του δεξιού κόλου είχαν μεγαλύτερη πιθανότητα να πάσχουν από σακχαρώδη διαβήτη (OR=3.31) και στεφανιαία νόσο (p=0.056). Η βλεννώδης διαφοροποίηση ήταν πιο συχνή στην δεξιά υποομάδα (OR=4,49), όπως και ο αριθμός των διηθημένων λεμφαδένων (p = 0.039), ενώ η υψηλή διαφοροποίηση ήταν πιο συχνή στην αριστερή υποομάδα (OR=2,78). Οι RAS wild type ασθενείς που έλαβαν anti-EGFR αγωγή εμφάνισαν μεγαλύτερο όφελος (PFS: 16.5 μήνες) συγκριτικά με όσους έλαβαν anti-VEGF αγωγή (PFS: 13.7 μήνες) (p=0,05), ενώ μεταξύ RAS wild-type ασθενών που έλαβαν anti-EGFR αγωγή, οι ασθενείς με αριστερή εντόπιση εμφάνισαν μεγαλύτερο όφελος (PFS: 15.8 μήνες) από τους ασθενείς με δεξιά εντόπιση (PFS: 5.5 μήνες) στην πρώτη γραμμή χημειοθεραπείας (p=0.034). Oι BRAF mutant ασθενείς εμφάνισαν συντομότερη χρονική περίοδο ελεύθερη επιβίωσης (9.3 μήνες) συγκριτικά με τους BRAF wild type ασθενείς (14.5 μήνες) (p=0,033) στην πρώτη γραμμή χημειοθεραπείας. Οι ασθενείς με καρκίνο του δεξιού κόλου παρουσίασαν υποτροπή σε μικρότερο χρονικό διάστημα (7.7 μήνες) συγκριτικά με τους ασθενείς με αριστερή εντόπιση (14.5 μήνες) (p<0,001) καθώς και συντομότερη ολική επιβίωση (δεξιό κόλον: 58.4 μήνες, αριστερό κόλον: 82.4 μήνες, p=0.018). Συμπέρασμα: Οι ασθενείς με καρκίνο του δεξιού τμήματος του παχέος εντέρου εμφανίζουν περισσότερα συνοδά νοσήματα, χειρότερα ιστολογικά και μοριακά χαρακτηριστικά και συνεπώς υψηλότερη πιθανότητα υποτροπής, πτωχής ανταπόκρισης στη στοχευμένη θεραπεία και συντομότερη ολική επιβίωση από τους ασθενείς με καρκίνο του αριστερού τμήματος του παχέος εντέρου.

Inhibition of MERTK Promotes Suppression of Tumor Growth in BRAF Mutant and BRAF Wild-Type Melanoma

Molecular Cancer Therapeutics ◽

10.1158/1535-7163.mct-18-0456 ◽

2018 ◽

Vol 18 (2) ◽

pp. 278-288 ◽

Cited By ~ 5

Author(s):

Lenka Sinik ◽

Katherine A. Minson ◽

John J. Tentler ◽

Jacqueline Carrico ◽

Stacey M. Bagby ◽

...

Keyword(s):

Tumor Growth ◽

Wild Type ◽

FRESCO-2: A global phase III study of the efficacy and safety of fruquintinib in patients (pts) with metastatic colorectal cancer (mCRC).

10.1200/jco.2021.39.3_suppl.tps154 ◽

2021 ◽

Vol 39 (3_suppl) ◽

pp. TPS154-TPS154

Author(s):

Arvind Dasari ◽

James C. Yao ◽

Alberto F. Sobrero ◽

Takayuki Yoshino ◽

William R. Schelman ◽

...

Keyword(s):

Clinical Trial ◽

Growth Factor ◽

Phase Iii ◽

Controlled Study ◽

Efficacy And Safety ◽

Wild Type ◽

Phase 3 ◽

Prior Therapy ◽

Anti Vegf ◽

The Us

TPS154 Background: Pts with mCRC have limited treatment options following progression on standard therapies. Current standard of care (SOC) after pts progress on trifluridine/tipiracil (TAS-102) or regorafenib is re-challenge with previous systemic treatments, enrollment in a clinical trial, or best supportive care (BSC). Fruquintinib (Elunate) is a novel, highly selective, vascular endothelial growth factor (VEGF) receptor (VEGFR)-1, -2, and -3 tyrosine kinase inhibitor (TKI) ( Cancer Biol Ther 2014;15:1635-1645). Fruquintinib is approved in China to treat pts with mCRC who received or are intolerant to fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, anti-VEGF therapy, and, if RAS wild type, anti-epidermal growth factor receptor (EGFR) therapy. Approval was based on results of the phase 3 FRESCO study (2013-013-00CH1; NCT02314819; JAMA 2018;319:2486-2496), in which fruquintinib 5 mg daily (QD), 3 weeks on, 1 week off (3 on/1 off), significantly improved overall survival (OS) in pts with mCRC in the 3rd-line+ setting when compared to placebo (median OS 9.3 months [mo] versus 6.6 mo; hazard ratio [HR] 0.65; p < .001). Progression-free survival (PFS) was also superior (median PFS 3.7 mo versus 1.8 mo; HR 0.26; p < .001). The toxicities of fruquintinib were consistent with those of other VEGF TKIs and were manageable. At the time FRESCO was conducted in China, SOC for pts with mCRC differed from that in the US, EU, and Japan. We describe here a global phase 3 study (FRESCO-2; 2019-013-GLOB1; NCT04322539) being conducted to investigate fruquintinib’s efficacy and safety in pts with refractory mCRC and a treatment profile representative of the global SOC. Methods: FRESCO-2 is a randomized, double-blind, placebo-controlled study to compare fruquintinib + BSC to placebo + BSC. Key inclusion criteria are progression on or intolerance to treatment with TAS-102 and/or regorafenib; previous treatment with standard approved therapies including chemotherapy, anti-VEGF therapy, and, if RAS wild type, anti-EGFR therapy. Prior therapy with immune checkpoint or BRAF inhibitors is required for pts with corresponding tumor alterations. Pts (~522) will be randomized 2:1 to receive either fruquintinib 5 mg orally (PO) QD + BSC or placebo 5 mg PO QD + BSC, with a 3 on/1 off schedule. Randomization will be stratified by prior therapy, RAS status, and duration of metastatic disease. The primary endpoint is OS; secondary endpoints include PFS, disease control rate, objective response rate, duration of response, and safety. Final OS analyses will be performed when 364 OS events are observed; futility analysis will be conducted with 1/3 (121) OS events. If enrichment of post-regorafenib pts occurs, enrollment to that strata will be capped at approximately 262. FRESCO-2 will be activated in the US, EU, and Japan; global enrollment is anticipated over 13 mo. Clinical trial information: NCT04322539.

Systemic Therapy for Melanoma: ASCO Guideline

10.1200/jco.20.00198 ◽

2020 ◽

Vol 38 (33) ◽

pp. 3947-3970 ◽

Cited By ~ 14

Author(s):

Rahul Seth ◽

Hans Messersmith ◽

Varinder Kaur ◽

John M. Kirkwood ◽

Ragini Kudchadkar ◽

...

Keyword(s):

Systematic Review ◽

Systemic Therapy ◽

Cutaneous Melanoma ◽

Meta Analysis ◽

Mek Inhibitor ◽

Wild Type ◽

Additional Information ◽

Metastatic Setting ◽

Wide Range ◽

PURPOSE To provide guidance to clinicians regarding the use of systemic therapy for melanoma. METHODS ASCO convened an Expert Panel and conducted a systematic review of the literature. RESULTS A systematic review, one meta-analysis, and 34 additional randomized trials were identified. The published studies included a wide range of systemic therapies in cutaneous and noncutaneous melanoma. RECOMMENDATIONS In the adjuvant setting, nivolumab or pembrolizumab should be offered to patients with resected stage IIIA/B/C/D BRAF wild-type cutaneous melanoma, while either of those two agents or the combination of dabrafenib and trametinib should be offered in BRAF-mutant disease. No recommendation could be made for or against the use of neoadjuvant therapy in cutaneous melanoma. In the unresectable/metastatic setting, ipilimumab plus nivolumab, nivolumab alone, or pembrolizumab alone should be offered to patients with BRAF wild-type cutaneous melanoma, while those three regimens or combination BRAF/MEK inhibitor therapy with dabrafenib/trametinib, encorafenib/binimetinib, or vemurafenib/cobimetinib should be offered in BRAF-mutant disease. Patients with mucosal melanoma may be offered the same therapies recommended for cutaneous melanoma. No recommendation could be made for or against specific therapy for uveal melanoma. Additional information is available at www.asco.org/melanoma-guidelines .

7 Assessing melanoma BRAF status through ddPCR of cfDNA

Postgraduate Medical Journal ◽

10.1136/postgradmedj-2019-fpm.7 ◽

2019 ◽

Vol 95 (1130) ◽

pp. 686.4-687

Author(s):

Lauren Passy ◽

Shobha Silva ◽

Ian Brock ◽

Greg Wells ◽

Angela Cox ◽

...

Keyword(s):

Braf Mutation ◽

Limit Of Detection ◽

Wild Type ◽

Braf Mutations ◽

Mutation Status ◽

Gapdh Gene ◽

Fractional Abundance ◽

Significant Difference ◽

Tissue Specimens ◽

IntroductionTreatment of recurrent and metastatic melanoma has been revolutionised by targeted therapy. Inhibitors of mutant BRAF are a systemic treatment offered for patients with stage III/IV melanoma who are known to carry a mutation in BRAF. Currently patients’ BRAF mutation status is assessed through molecular analysis of tissue specimens.Cell-free DNA (cfDNA) released from tumours can be used to non-invasively detect active disease and predict survival in melanoma. cfDNA also provides a method for detecting BRAF mutations. This project aimed to ascertain BRAF mutation status in cfDNA through digital droplet PCR (ddPCR) of plasma samples from patients with melanoma. We aimed to assess the relationship between cfDNA BRAF positivity and disease relapse and progression.MethodsPlasma from 100 patients with active or recently resected melanoma was obtained during previous work. 85 samples had cfDNA extracted. Tissue BRAF status was known for 57 samples. cfDNA was extracted from 1–2 ml plasma with the QIAamp circulating nucleic acid kit (QIAGEN®) following manufacturer protocol, eluting cfDNA into 100µL. cfDNA was quantified with SYBR green quantitative real-time PCR (Life Technologies), based on an 87bp GAPDH gene amplicon. ddPCR™ was performed using the Bio-Rad QX200 Droplet Generator™ and Droplet Reader as per manufacturer protocol. Analysis was performed with Bio-Rad QuantaSoft Version 1.7.4.ResultsMedian yield of cfDNA extracted from 85 samples was 1.97 ng/ml when eluted into 100µL. This was well-correlated with previous cfDNA extraction yields from this sample set (Pearson’s r=0.6687, p<0.0005), where a 200µL elution volume was used. 74 samples yielded >10,000 droplets and were included for analysis. 12 samples contained BRAF mutant positive droplets. A 74% concordance rate between tissue BRAF mutation status and the presence/absence of cfDNA BRAF mutant positive droplets was found. 7/18 tissue BRAF mutant samples contained BRAF mutant droplets, in comparison to 2/32 tissue BRAF wild-type samples. The presence of BRAF mutant positive droplets was significantly different between the tissue BRAF mutant and tissue BRAF wild-type groups (χ2 8.3145, p=0.004).Fractional abundance of BRAF mutant droplets in the samples containing mutant droplets ranged from 0.07–0.74%. When comparing BRAF mutant droplet-containing samples and samples without BRAF mutant droplets, there was no significant difference in rate of relapse (χ2 0.0948, p=0.758), nor mortality rate (χ2 3.3959, p=0.654).Conclusion cfDNA provides a non-invasive snapshot of the tumour genome and any potential therapeutic targets held within. This work demonstrates that a very low volume of cfDNA can be used to detect BRAF mutations in patients with melanoma through ddPCR.Previous work assessing BRAF status in cfDNA has used larger volumes of cfDNA. Though our concordance rates are comparable with other studies, it is possible that using a smaller amount of cfDNA in our ddPCR has resulted in some samples being below the limit of detection for ddPCR.Longitudinal study is warranted to monitor cfDNA BRAF status and mutant fractional abundance, and whether this better correlates with relapse of disease and disease progression.

BRAF mutation as a pejorative marker in metastatic melanoma.

10.1200/jco.2012.30.15_suppl.8555 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 8555-8555 ◽

Cited By ~ 1

Author(s):

Sophie Brissy ◽

Caroline Gaudy-Marqueste ◽

Stéphanie Mallet ◽

Sandrine Monestier ◽

Sylvie Hesse ◽

...

Keyword(s):

Overall Survival ◽

Multivariate Analysis ◽

Metastatic Melanoma ◽

Distant Metastasis ◽

Braf Mutation ◽

Cox Model ◽

Primary Melanoma ◽

Wild Type ◽

Significant Difference ◽

8555 Background: BRAF mutation in melanoma has been shown to be associated with a trend in favour of a spontaneous worse outcome after metastases in a series of 197 patients in Australia. Objective: To correlate BRAF status in metastatic melanoma with clinicopathologic features and outcome. Methods: In our department in France 182 patients with metastatic melanoma have been tested for BRAF mutation between September 2009 and September 2011. Survival was assessed by log-rank test. Multivariate analysis was performed with Cox model. Results: From 182 patients, 88 (48.3%) were B-RAF mutant; 77 (87.5%) V600E, 4 (4.5%) V600K, and 7 (8%) other mutation subtypes. BRAF-mutant patients were younger than BRAF wild-type patients at diagnosis of primary melanoma (median age 52.3 vs 60.7 years, respectively, p=0.003), and at diagnosis of distant metastasis (median age 53.6 vs 64.1 years respectively, p=0.002). 34 patients were treated by B-RAF inhibitors. There was no significant difference in other demographic features of patients with metastatic melanoma by mutation status. Features of the primary melanoma significantly associated with a BRAF mutation (p<0.05) were histopathologic subtype (SSM), high mitotic rate (≥1/mm2), lower Breslow thickness (median Breslow: 2.2 vs 3.5 mm for BRAF mutant and BRAF-wild-type patients respectively, p=0.016), truncal location and location on occasionally exposed at sun site.The interval from diagnosis of first ever melanoma to first distant metastasis was not significantly different in BRAF-mutant and wild-type patients. The median overall survival (OS) from diagnosis of primary melanoma was 6.5 years for BRAF wild-type patients. Median OS was not reached in BRAF-mutant patients treated (34 of 88) with a BRAF inhibitor, but also in those not treated (p=0.24, and p=0.06 for treated BRAF-mutant vs BRAF wild-type). The overall survival from diagnosis of first distant metastasis was not significantly different (p=0.75). These results remained unchanged in a multivariate analysis. Conclusions: Our results confirm the characteristics of BRAF-mutant metastatic patients, and the efficacy of B-RAF inhibitors, but not that the presence of mutant-BRAF is per se a pejorative predictive marker.

Phase III randomized trial of cetuximab (CET) plus either brivanib alaninate (BRIV) or placebo in patients (pts) with metastatic (MET) chemotherapy refractory K-RAS wild-type (WT) colorectal carcinoma (CRC): The NCIC Clinical Trials Group and AGITG CO.20 trial.

10.1200/jco.2012.30.4_suppl.386 ◽

2012 ◽

Vol 30 (4_suppl) ◽

pp. 386-386 ◽

Cited By ~ 8

Author(s):

Lillian L. Siu ◽

Jeremy D. Shapiro ◽

Derek J. Jonker ◽

Christos Stelios Karapetis ◽

John Raymond Zalcberg ◽

...

Keyword(s):

Kinase Inhibitor ◽

Objective Response ◽

Dose Intensity ◽

Phase Iii ◽

Wild Type ◽

Fibroblast Growth Factor Receptors ◽

Positive Effects ◽

Anti Vegf ◽

Global Quality Of Life ◽

Grade 3

386 Background: The anti-EGFR monoclonal antibody CET has improved survival in pts with MET, chemotherapy refractory, K-RAS wild type (WT) CRC. The addition of BRIV, a tyrosine kinase inhibitor targeting vascular endothelial and fibroblast growth factor receptors (VEGFR/FGFR), to CET has shown encouraging activity in an early phase clinical trial. Methods: Pts with MET CRC previously treated with combination chemotherapy were randomized 1:1 to receive CET 400 mg/m2 IV loading dose followed by weekly maintenance of 250 mg/m2 plus either BRIV 800 mg PO daily (Arm A) or placebo (Arm B). Pts may have had 1 prior anti-VEGF, but no prior anti-EGFR therapy. The trial was amended shortly after opening to enrol K-RAS WT pts. Primary endpoint was overall survival (OS). Results: From 02/2008 to 02/2011, 750 pts were randomized (376 in Arm A and 374 in Arm B). Demographics: median age=64 (range 27-88); male=64%; ECOG 0:1:2 (%)=32:58:10; >3 prior chemotherapy regimens=92%; prior anti-VEGF therapy=41%; K-RAS WT=97%. Median OS in the intent-to-treat population was 8.8 months in Arm A and 8.1 months in Arm B, hazard ratio (HR)=0.88; 95% CI=0.74 to 1.03; p=0.12. Median progression-free survival (PFS) was 5.0 months in Arm A and 3.4 months in Arm B, HR=0.72; 95% CI=0.62 to 0.84; p<0.0001. Both partial responses (13.6% vs 7.2%, p=0.004) and stable disease (50% vs 44%) were higher in Arm A. Incidence of any ≥grade 3 adverse event (AE) was 78% in Arm A and 53% in Arm B. Most frequent ≥grade 3 AEs were fatigue (25%), hypertension (11%) and rash (10%) in Arm A, vs fatigue (11%), rash (5%) and dyspnea (5%) in Arm B. Time to deterioration of physical function was shorter and global quality of life scores were lower in Arm A vs Arm B. Pts received ≥90% dose intensity of CET=57% in Arm A vs 83% in Arm B; of BRIV/placebo=48% in Arm A vs 87% in Arm B. Conclusions: Despite positive effects on PFS and objective response, the combination of CET+BRIV did not significantly improve OS in pts with MET, chemotherapy refractory, K-RAS WT CRC. AEs were consistent with those reported for each drug given as monotherapy.

Withholding anti-EGFR, the impact on outcome in RAS wild-type metastatic colorectal tumors (WAIT or ACT trial).

10.1200/jco.2019.37.4_suppl.626 ◽

2019 ◽

Vol 37 (4_suppl) ◽

pp. 626-626

Author(s):

Lola-Jade Palmieri ◽

Laurent Mineur ◽

David Tougeron ◽

Benoit Rousseau ◽

Victoire Granger ◽

...

Keyword(s):

Growth Factor ◽

Propensity Score ◽

Cohort Analysis ◽

Wild Type ◽

First Line ◽

Anti Vegf ◽

Ras Status ◽

Metastatic Sites ◽

The Impact ◽

Doublet Chemotherapy

626 Background: First line of RAS wild-type (WT) unresectable metastatic colorectal cancer (mCRC) can be doublet chemotherapy with an anti-VEGF (Vascular Endothelial Growth Factor), or an anti-EGFR (Epidermal Growth Factor Receptor). Waiting for RAS status, many oncologists initiate chemotherapy and add the anti-EGFR secondly. The objective was to compare the delayed introduction of the anti-EGFR to the immediate introduction of the anti-VEGF in first-line treatment of RAS WT mCRC. Methods: This was a retrospective cohort analysis from 2013 to 2016, multicentric with 28 health care centers. We included patients with RAS WT unresectable mCRC treated between 2013 and 2016 by a doublet chemotherapy with the anti-VEGF introduced immediately or with the anti-EGFR introduced at C2 or C3. Progression free survival (PFS), overall survival (OS) and response rate (RR) for the two cohorts were compared. Hazard ratios (HR) with 95% confidence interval (95%CI) were estimated with cox regression models weighted on propensity score to deal with potential confounders. Results: A total of 262 patients were included, 129 in the immediate anti-VEGF group and 133 in the delayed anti-EGFR group. Median follow-up was 37.9 months. Ninety-two patients had the anti-EGFR introduced at C2, 40 at C3. The median delay of RAS analysis was 19 days (q1-q3: 13-26). Patients treated with anti-VEGFs were more likely men (68% versus 56%), with more metastatic sites ( > 2 sites: 15% versus 9%). A propensity score including the number of metastatic sites and a possible previous treatment was built. Delayed anti-EGFRs were associated with longer PFS compared to immediate anti-VEGFs: 13.8 versus 11.0 months, p = 0.0244. After weighting, delayed anti-EGFRs were still associated with better PFS: HR 0.74, 95%CI [0.61 – 0.90], p = 0.0024. OS was not different between the two arms (30.5 for anti-VEGF versus 29.9 months, p = 0.3934), even after weighting (HR 0.86, 95%CI [0.69 – 1.08], p = 0.2024). There was a better RR with delayed anti-EGFRs: 66.7% versus 45.6%, p = 0.0007. Conclusions: Our findings suggest that, while waiting for RAS status, the delayed introduction of the anti-EGFR is a valid option, compared to the immediate introduction of the anti-VEGF.

Value of Mismatch Repair, KRAS, and BRAF Mutations in Predicting Recurrence and Benefits From Chemotherapy in Colorectal Cancer

10.1200/jco.2010.30.1366 ◽

2011 ◽

Vol 29 (10) ◽

pp. 1261-1270 ◽

Cited By ~ 409

Author(s):

Gordon Hutchins ◽

Katie Southward ◽

Kelly Handley ◽

Laura Magill ◽

Claire Beaumont ◽

...

Keyword(s):

Colorectal Cancer ◽

Mismatch Repair ◽

Mutational Analysis ◽

Left Colon ◽

Rectal Tumors ◽

Wild Type ◽

Right Colon ◽

Kras Mutations ◽

Risk Of Recurrence ◽

Purpose It is uncertain whether modest benefits from adjuvant chemotherapy in stage II colorectal cancer justify the toxicity, cost, and inconvenience. We investigated the usefulness of defective mismatch repair (dMMR), BRAF, and KRAS mutations in predicting tumor recurrence and sensitivity to chemotherapy. Patients and Methods Immunohistochemistry for dMMR and pyrosequencing for KRAS/BRAF were performed for 1,913 patients randomly assigned between fluorouracil and folinic acid chemotherapy and no chemotherapy in the Quick and Simple and Reliable (QUASAR) trial. Results Twenty-six percent of 695 right-sided colon, 3% of 685 left-sided colon, and 1% of 407 rectal tumors were dMMR. Similarly, 17% of right colon, 2% of left colon, and 2% of rectal tumors were BRAF mutant. KRAS mutant tumors were more evenly distributed: 40% right colon, 28% left colon, and 36% rectal tumors. Recurrence rate for dMMR tumors was half that for MMR-proficient tumors (11% [25 of 218] v 26% [438 of 1,695] recurred; risk ratio [RR], 0.53; 95% CI, 0.40 to 0.70; P < .001). Risk of recurrence was also significantly higher for KRAS mutant than KRAS wild-type tumors (28% [150 of 542] v 21% [219 of 1,041]; RR, 1.40; 95% CI, 1.12 to 1.74; P = .002) but did not differ significantly between BRAF mutant and wild-type tumors (P = .36). No marker predicted benefit from chemotherapy with efficacy not differing significantly by MMR, KRAS, or BRAF status. The prognostic value of MMR and KRAS was similar in the presence and absence of chemotherapy. Conclusion MMR assays identify patients with a low risk of recurrence. KRAS mutational analysis provides useful additional risk stratification to guide use of chemotherapy.

THER-10. IMPACT OF BRAF MUTATIONAL STATUS ON THE EFFICACY OF IMMUNOTHERAPY FOR MELANOMA BRAIN METASTASES

Neuro-Oncology Advances ◽

10.1093/noajnl/vdz014.053 ◽

2019 ◽

Vol 1 (Supplement_1) ◽

pp. i12-i13

Author(s):

Adam Lauko ◽

Soumya Sagar ◽

Addison Barnett ◽

Wei Wei ◽

Samuel Chao ◽

...

Keyword(s):

Brain Metastases ◽

Tertiary Care ◽

Rank Test ◽

P Value ◽

Wild Type ◽

Braf Mutations ◽

Mutational Status ◽

Melanoma Brain Metastases ◽

Melanoma Patients ◽

Abstract BACKGROUND: BRAF mutations occur in 50% of melanoma patients. Targeted agents – BRAF and MEK inhibitors and immunotherapy improve survival of melanoma patients with BRAF mutations. These agents have intracranial efficacy as shown in clinical trials. However, the efficacy of immunotherapies (immune checkpoint blockade) in melanoma brain metastases and the correlation with BRAF status is not as well characterized. METHODS: We reviewed 351 patients with melanoma brain metastases treated at our tertiary care center between 2000 and 2018, 75 of which received immunotherapy with known BRAF mutational status. Two-year, 5-year, and median overall survival (OS) was calculated from the start of immunotherapy to compare the efficacy of immunotherapy in BRAF mutant and BRAF wild type patients using the log-rank test. RESULTS: At the time of diagnosis of brain metastasis, the median age was 61 (23–87) years, median KPS was 80 (50–100), number of intracranial lesions was 2 (1–15), and 79% had extra-cranial metastases. Sixty-three patients were treated with stereotactic radiosurgery (SRS), 27 underwent whole brain radiation (WBRT) and 21 underwent surgery. When treated with immunotherapy, BRAF mutant and BRAF wild type median survival was 15.7 months (95% CI=9.4 – 42.4) and 6.9 (95% CI=4.1– 26.7) months (p-value=0.205), respectively. Two-year BRAF mutant and BRAF wild type survival was 35% (95% CI=21 – 58) and 28% (95% CI=16 – 51), and 5-year survival was 22% (95% CI=10 – 46) and 23% (95% CI=11 – 47), respectively. CONCLUSIONS: Twenty percent of patients with BRAF mutant and BRAF wild-type patients treated with immunotherapy derive a long-term benefit from immunotherapy and multimodality treatment and are alive 5 years from diagnosis of brain metastases. This was rarely seen in the pre-immunotherapy era in melanoma brain metastases. There was no difference in outcome based on the BRAF mutational status with use of immunotherapy in melanoma brain metastases.