Clinical features and response to immune checkpoint inhibitors (ICIs) in pregnancy-associated melanoma (PAM).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9564-9564
Author(s):  
Daniel Ying Wang ◽  
Carina N. Owen ◽  
David James Palmieri ◽  
Justine Vanessa Cohen ◽  
Zeynep Eroglu ◽  
...  
Keyword(s):  
Retrospective Study ◽  
Rna Sequencing ◽  
Checkpoint Inhibitors ◽  
Post Partum ◽  
Primary Melanoma ◽  
Progression Free Survival ◽  
Molecular Data ◽  
Advanced Melanoma ◽  
Braf V600e ◽  
Molecular Features

9564 Background: Melanoma is one of the most common malignancies diagnosed during pregnancy. Little is known about the clinical outcomes of PAM, in particular, response to ICIs. We performed a retrospective study to assess this issue. Methods: A multicenter retrospective study was performed at 4 large melanoma centers. Patients (pts) with PAM treated with ICIs were identified and examined. Clinical data and molecular data (RNA sequencing, IHC) were explored. PAM was defined as development of advanced melanoma during pregnancy or within 2 years post-partum. Results: 19 pts with PAM were treated with ICIs. Median follow-up was 11.7 months (range 1.4 – 41.9 months). Median age was 29 years (range 16-36). Most pts had a cutaneous primary (N = 17, 89%) including the extremity (N = 8) or trunk (N = 7), and 5% were occult. 11 pts (58%) had a BRAF V600E mutation and 6 (32%) pts received BRAF/MEK targeted therapy. Most pts had prior primary melanoma (N = 12, 63%) and presented with advanced melanoma in the post-partum setting (N = 11, 58%). At advanced presentation, 6 (32%) pts were stage III/M1a and 13 (68%) pts were stage M1b/c/d; 7 (41%) pts had elevated LDH and 13 (68%) had visceral involvement. Among 11 patients treated with combination ipilimumab + anti-PD-1 therapy, 7 (64%) had objective responses (OR) with a 1-year progression free survival (PFS) of 40% and 1-year overall survival (OS) of 100%. By contrast, ICI monotherapy (3 with anti-PD-1/L1 and 4 with ipilimumab) was associated with poorer outcomes (OR in 25% and 33% for ipilimumab and anti-PD-1/L1, respectively). Molecular features (RNA sequencing, immunohistochemistry) will be presented. Conclusions: Patients with PAM represent a unique population and may particularly benefit with combination ICI therapy compared with ICI monotherapy (in a limited sample size). Molecular underpinnings of PAM biology are still being elucidated.

A phase Ib study of napabucasin plus weekly paclitaxel in patients with advanced melanoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9553-9553
Author(s):  
William Jeffery Edenfield ◽  
Carlos Becerra ◽  
Fadi S. Braiteh ◽  
Alexander I. Spira ◽  
Ryan J. Sullivan ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Braf Inhibitor ◽  
Progression Free Survival ◽  
Advanced Melanoma ◽  
Braf V600e ◽  
Weekly Paclitaxel ◽  
Combination Regimen ◽  
Clinical Safety ◽  
Grade 3 ◽  
Anti Tumor Activity

9553 Background: Napabucasin is a first-in-class cancer stemness inhibitor, identified by its ability to inhibit STAT3-driven gene transcription and spherogenesis of cancer stem cells (Li et al PNAS 112 (6):1839, 2015). Synergistic anti-tumor activity with paclitaxel was observed in pre-clinical testing, and a favorable clinical safety profile was established in a phase I/II trial in patients (pts) with advanced solid tumors. A phase 1b trial was established to evaluate the safety and preliminary signs of anti-cancer activity of the combination regimen in pts with advanced melanoma. Methods: Pts with melanoma were enrolled after failure of standard therapies for advanced disease. Napabucasin 480 or 500 mg orally twice daily was administered with paclitaxel 80 mg/m2 IV weekly for 3 of every 4 weeks. Adverse events were evaluated using CTCAE v4.03 and objective tumor assessments were obtained every 8 weeks and evaluated per RECIST 1.1 criteria. Results: A total of 12 pts with advanced melanoma were enrolled after a median 3 prior lines of therapy (including immune checkpoint inhibitors, BRAF-inhibitor if presence of BRAF V600E mutation). Protocol therapy was well tolerated with grade 3 AEs including diarrhea (n = 3), abdominal pain (n = 1), and fatigue (n = 1). Partial response (PR) was observed in 1 pt. Stable disease of at least 24 weeks or more was achieved by 33% of patients (n = 4) and the median progression-free survival (mPFS) was 3.7 months. Prolonged survival of 1 year or more was achieved by 33% of pts (n = 4), with a median overall survival (mOS) of 10.4 months. Conclusions: Napabucasin plus weekly paclitaxel has shown clinical safety and encouraging anti-tumor activity in a cohort of pts with previously treated advanced melanoma. The RP2D in combination with weekly paclitaxel was established to 480 mg orally bid. The data suggest that targeting stemness pathways with napabucasin may be a novel therapeutic strategy for melanoma. Clinical trial information: NCT01325441.

Primary (1°) tumor location as an independent prognostic marker from molecular features for overall survival (OS) in patients (pts) with metastatic colorectal cancer (mCRC): Analysis of CALGB / SWOG 80405 (Alliance).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3503-3503 ◽  
Author(s):  
Alan P. Venook ◽  
Fang-Shu Ou ◽  
Heinz-Josef Lenz ◽  
Omar Kabbarah ◽  
Xueping Qu ◽  
...  
Keyword(s):  
Prognostic Marker ◽  
Molecular Subtype ◽  
Progression Free Survival ◽  
Molecular Data ◽  
Tumor Location ◽  
Tumor Burden ◽  
Independent Prognostic Marker ◽  
Molecular Features ◽  
Metastatic Sites ◽  
The Impact

3503 Background: 80405 found no OS or Progression Free Survival (PFS) difference when bevacizumab (BV) or cetuximab (Cet) was added to 1st-line FOLFOX or FOLFIRI in All RAS wild type (wt) mCRC pts. There was a significant 1° side by biologic interaction (P int: OS = 0.008, PFS = 0.001) favoring pts with left-sided (L) 1°. Analyses of 1° tumors beyond All RAS includes Consensus Molecular Subtype (CMS), BRAF and MSI. (CMS results - see Lenz et al; BRAF -see Innocenti et al) We asked whether 1° tumor location - L vs right (R) - is an independent prognostic marker when these other molecular features are considered. Methods: We used a Cox proportional hazard model stratified by prior XRT and +/- adjuvant chemo; adjusted for age, gender, synchronous vs metachronous, CMS, MSI and BRAF status. Pts with transverse (T) tumors were excluded in this analysis. Results: Sidedness was determined in 782 pts (L - 472; R - 256; T -54). Molecular data from 728 pts (with L - and R-sided 1°s) was available as follows: KRAS -- 291, NRAS -393, BRAF - 393, MSI - 378, CMS - 533. L vs R mOS: 32.9 v 19.6 months (mo) (p < 0.0001). See Table for OS results in All RAS / BRAF wt and BRAF mutant (mut) pts. Sidedness (R vs L) is an independent prognostic marker even after adjusting for all these molecular features: HR = 1.392 (1.032, 1.878), p = 0.031. Conclusions: Primary tumor location is an independent prognostic factor when adjusted for age, gender, synchronous/metachronous, CMS, MSI and BRAF status. We are exploring clinical variables such as tumor burden, metastatic sites and measurability of disease in an attempt to explain the impact of sidedness. Support: U10CA188021, U10CA180882. Eli Lilly and Co, Genentech/Roche, Pfizer, Sanofi. Clinical trial information: NCT002655850. [Table: see text]

Host metabolic factors and prognosis in patients treated with immune checkpoint inhibitors for advanced malignancies.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14162-e14162
Author(s):  
Federica Biello ◽  
Marco Audisio ◽  
Silvia Genestroni ◽  
Gloria Borra ◽  
Francesca D'Avanzo ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Multivariable Analysis ◽  
Progression Free Survival ◽  
Fold Increase ◽  
Advanced Melanoma ◽  
Host Metabolism ◽  
Increase In Risk

e14162 Background: It is well established that an altered host metabolism has an impact on cancer outcome, possibly mediated by several mechanisms, including hyperglicaemia, hyperinsulinemia and presence of chronic inflammation. The aim of our analysis was to evaluate the correlation between host metabolism and clinical outcome in patients with advanced melanoma, kidney and non-small cell lung cancer (NSCLC), treated with immune checkpoint inhibitors (anti-CTLA4, anti PD1 and anti PDL1). Methods: The relationship between presence of type 2 diabetes mellitus (DMII) at baseline and outcome was assessed in 187 patients treated with immune checkpoint inhibitors in two cancer centers. Progression Free Survival (PFS) and Overall Survival (OS) were calculated by Kaplan-Meier estimation; multivariate Cox analysis was performed according to age, gender, BMI (normal < 25 kg/m2, overweight 25-30 kg/m2, obese > 30 kg/m2), type of cancer and line of treatment. Results: One-hundred-sixty-eight patients were available for our analysis. Twenty-eight patients (17%) were diabetic at baseline. Median age was 65 (range 25-80); 83 patients were males (49%); 82 (48%) had advanced melanoma, 83 (49%) NSCLC and 3 (3%) kidney cancer. One-hundred-two (60%) patients had BMI < 25, 51 (30%) were overweight and 16 (10%) were obese. The first line of treatment was immunotherapy in 83 (49%) patients. By univariable analysis median PFS was 4.2 months in non diabetics vs 6.4 in diabetics patients (HR 0.95; 95%CI 0.58-1.58); median OS was 6.17 and 9.1 months, respectively (HR 1.00; 95%CI 0.58-1.75). At multivariable analysis, taking into account DMII, BMI, sex, age, line of treatment and type of cancer, we found that BMI ≤25 was associated with a two fold increase in risk of progression (PD) or death (p = 0.005), whereas patients who received immunotherapy as second or subsequent line had a two fold increase in risk of PD or death (p = 0.003). Conclusions: The results of our analysis show that in patients with advanced cancer treated with immune checkpoint inhibitors, the presence of DMII does not adversely affect the clinical outcome. Conversely, lower BMI was associated with a significantly worse PFS and OS, independently from type of cancer, age and gender. As expected, patients who received immunotherapy in later lines of treatment had a significantly shorter survival.

scholarly journals Antibiotics are associated with decreased progression-free survival of advanced melanoma patients treated with immune checkpoint inhibitors

2019 ◽  
Vol 8 (4) ◽  
pp. e1568812 ◽  
Author(s):  
Arielle Elkrief ◽  
Layal El Raichani ◽  
Corentin Richard ◽  
Meriem Messaoudene ◽  
Wiam Belkaid ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Progression Free Survival ◽  
Advanced Melanoma ◽  
Free Survival ◽  
Melanoma Patients

scholarly journals The effect of antibiotics on the clinical outcomes of patients with solid cancers undergoing immune checkpoint inhibitor treatment: a retrospective study

BMC Cancer ◽  
2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Hyunho Kim ◽  
Ji Eun Lee ◽  
Sook Hee Hong ◽  
Myung Ah. Lee ◽  
Jin Hyoung Kang ◽  
...  
Keyword(s):  
Retrospective Study ◽  
Clinical Outcomes ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Small Cell Lung Carcinoma ◽  
Objective Response ◽  
Progression Free Survival ◽  
Solid Cancer ◽  
Cell Lung Carcinoma ◽  
Antibiotics Use

Abstract Background This study aimed to assess the effect of antibiotics on the clinical outcomes of patients with solid cancers undergoing treatment with immune checkpoint inhibitors (ICIs). Methods The medical records of 234 patients treated with ICIs for any type of solid cancer between February 2012 and May 2018 at the Seoul St. Mary’s Hospital were retrospectively reviewed. The data of patients who received antibiotics within 60 days before the initiation of ICI treatment were analyzed. The patients’ responses to ICI treatment and their survival were evaluated. Results Non-small-cell lung carcinoma was the most common type of cancer. About half of the patients were treated with nivolumab (51.9%), and cephalosporin (35.2%) was the most commonly used class of antibiotics. The total objective response rate was 21%. Antibiotics use was associated with a decreased objective response (odds ratio 0.466, 95% confidence interval [CI] 0.225–0.968, p = 0.040). The antibiotics group exhibited shorter progression-free survival (PFS) and overall survival (OS) than the no antibiotics group (median PFS: 2 months vs. 4 months, p < 0.001; median OS: 5 months vs. 17 months, p < 0.001). In the multivariate analysis, antibiotics use was a significant predictor of patient survival (PFS: hazard ratio [HR] 1.715, 95% CI 1.264–2.326, p = 0.001; OS: HR 1.785, 95% CI 1.265–2.519, p = 0.001). Conclusions The use of antibiotics may affect the clinical outcomes of patients with solid cancers treated with ICIs. Careful prescription of antibiotics is warranted in candidates who are scheduled for ICI treatment. Trial registration Not applicable (retrospective study).

PD-L1 and CD8 expression and association with outcomes in patients (pts) with BRAF V600E/K-mutant metastatic melanoma (MM) who received dabrafenib + trametinib (D+T) in the randomized phase 3 COMBI-v study.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9527-9527 ◽  
Author(s):  
Dirk Schadendorf ◽  
Georgina V. Long ◽  
Jean Jacques Grob ◽  
Paul D. Nathan ◽  
Antoni Ribas ◽  
...  
Keyword(s):  
Clinical Benefit ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Expression Profiles ◽  
Progression Free Survival ◽  
Inflammatory Cells ◽  
Braf V600e ◽  
Phase 3 ◽  
Stromal Compartment ◽  
Duration Of Response

9527 Background: The phase 3 COMBI-v study (NCT01597908) showed that D+T significantly improved outcomes vs vemurafenib in pts with BRAFV600E/K–mutant MM. Checkpoint inhibitors also provide clinical benefit in some pts with MM. To date, characterization of markers associated with response to anti–PD-1 therapy has identified positive associations with PD-L1 expression and immune cell infiltration. Here we describe expression of PD-L1 and the T-cell marker CD8 in tumor samples from pts randomized to receive D+T in COMBI-v and associations with clinical outcomes. Methods: Biopsies from 74 of 352 D+T pts (21%) in COMBI-v were assessed for expression of PD-L1 (PD-L1 IHC 22C3 pharmDx assay; Dako) and CD8 (anti-CD8 antibody, clone C8/144B; Dako). PD-L1 positivity was determined as a percentage of stained tumor cells and MEL score (staining on both tumor and mononuclear inflammatory cells; 0 or 1 [negative]: < 1% staining; 2-5 [positive]: ≥ 1% staining; Daud et al. J Clin Oncol. 2016). Results: Of 74 pts analyzed, 54 (73%) had PD-L1–positive tumors, and the largest MEL score subgroup was 2 (45%). A significant association ( P < .0001) was observed between PD-L1 and CD8 expression. Overall response rate, tumor shrinkage, progression-free survival, overall survival (OS), and duration of response with D+T were not associated with PD-L1 (MEL score of ≥ 2) or CD8 positivity. However, a significant association ( P = .04) with improved OS was observed in tumors with high PD-L1 expression (≥ 20% of cells PD-L1 positive), and a trend ( P = .06) was seen in pts with a MEL score of ≥ 3. Among PD-L1–negative pts, improved OS was seen in those with high CD8 positivity ( P = .03), particularly in the stromal compartment. Conclusions: These data, representing PD-L1 and CD8 expression profiles for a BRAF-mutant mm population in the context of outcomes following D+T, showed that clinical benefit was maintained regardless of immune phenotype. The results also suggest that an immune component has an impact on outcomes following targeted therapy. Clinical trial information: NCT01597908.

Retrospective study to assess the efficacy and safety of checkpoint inhibitors in advanced urothelial carcinoma in real-world setting.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e17043-e17043
Author(s):  
Elena Sevillano Fernandez ◽  
Javier Puente ◽  
Natalia Vidal ◽  
Alvaro Pinto ◽  
Lourdes Garcia Sanchez ◽  
...  
Keyword(s):  
Retrospective Study ◽  
Urothelial Carcinoma ◽  
Real World ◽  
Checkpoint Inhibitors ◽  
Progression Free Survival ◽  
Complete Response ◽  
Molecular Study ◽  
Collaborative Group ◽  
First Line ◽  
Advanced Urothelial Carcinoma

e17043 Background: Checkpoint Inhibitors (CPI) have become a new standard of treatment in advanced urothelial carcinoma. However, little is known regarding the outcome of patients in daily practice.We aimed to assess tumor response and toxicity of CPIs in a cohort of patients treated in “real world” conditions. In parallel, a comprehensive molecular study in tumor samples from these patients, is ongoing. Methods: We designed an observational retrospective study within the “Grupo Centro” collaborative group. Adult patients diagnosed of metastasic urothelial carcinoma (mUC) and treated with CPIs between 2011-2019 in any of the 20 centers of the group, were eligible. Results: Up to date 100 patients have been included (82% males) with a median age of 74 years (48 -96). In 82% patients primary was bladder cancer. Most common metastasic sites were bone (26%) and liver (16%).With a median follow up of 10,6 months(mo) median progression free survival (mPFS) was 6,6mo (1,4-95,4 range) and median Overall Survival (mOS) was 21.3mo (3,8-121,8). 38% of patients received CPIs in first line(L): atezolizumab:27, pembrolizumab: 10, nivolumab:1. The median number of cycles was 8,2. Up to 51% received platinum-based combinations in first line. 69% (69/100) pts received 2L treatment: 68% with CPIs, 27,5% with chemotherapy and 4% with FGFR inhibitors (as part of a clinical trial). 2L mPFS was 3,5 mo (1,9-25.9). 23% (23/100) patients received 3L, of them 26% (6/23) were treated with CPIs. 3L mPFS:8,3mo(0,4-43,8). As a whole, patients treated with CPI accross different lines, achieved complete response in 8% of the cases, partial response in 18% and stable disease in 15%. Up to 44% of cases presented progressive disease as best response and evaluation was not available in 15%. Most common G1-2 AEs related to immunotherapy were: asthenia:31%,pruritus:16% and anorexia: 9%.10% pts experienced G3-4 toxicity: asthenia G3: 4, diarrhea G3: 1, erythrodysesthesia G3:1, arthromyalgia G3: 1, cardiac arrest G4:1,pneumonitis G4:1,anemia G3:1. Conclusions: This study confirms the efficacy and security of CPIs in real world. Response rates and toxicity profile were comparable to those reported in clinical trials.

BRAF and NRAS mutation status and response to checkpoint inhibition in advanced melanoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9558-9558
Author(s):  
Olivier Jules van Not ◽  
Alfonsus Johannes Maria van den Eertwegh ◽  
John B. A. G. Haanen ◽  
Christian U. Blank ◽  
Maureen J.B. Aarts ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Cox Model ◽  
Objective Response ◽  
Progression Free Survival ◽  
Advanced Melanoma ◽  
Specific Gene ◽  
Wild Type ◽  
First Line ◽  
Nras Mutation ◽  
Braf Mutant

9558 Background: The ability to analyze tumor mutation profiles has altered the oncology treatment landscape over the past decades. However, little is known about the effect of specific gene mutations on the response to immune checkpoint inhibitors (ICIs) in patients with advanced melanoma. Methods: All unresectable stage IIIc and IV patients with BRAF V600, NRAS mutations and BRAF and NRAS wild-type patients treated with anti-PD-1 or ipilimumab-nivolumab between 2012 and 2020 were included from the Dutch Melanoma Treatment Registry, a nationwide population-based registry. Outcomes were objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). A Cox model was used to analyze the association of possible prognostic factors with PFS and OS. Results: In total 1358 first-line patients treated with anti-PD-1 and 524 treated with ipilimumab-nivolumab were included. Median follow-up was 25.6 months for anti-PD-1 treated patients and 16.3 months for ipilimumab-nivolumab treated patients. The highest ORR, in first-line, to anti-PD-1 was in patients who were BRAF and NRAS wildtype (50.2%), compared to BRAF V600 (43.8%) and NRAS mutated patients (49.8%). ORR to ipilimumab-nivolumab was highest in NRAS mutated patients (44.9%), while ORR was 39.5% for BRAF mutated patients and 40.3% for wild-type patients. Median PFS in the anti-PD-1 treatment regimen was significantly higher (p = 0.049) for double wild-type patients (16.7 months) patients than for BRAF mutated patients (9.9 months) and NRAS mutated patients (11.3 months). PFS was not significantly different (p = 0.11) in the ipilimumab-nivolumab treatment cohort, with a median PFS of 6.5 months for the wild-type group, 10.8 months for the BRAF group, and 9.1 months for the NRAS group. In the anti-PD-1 treated patients, median OS was significantly higher (p < 0.001) for BRAF mutated patients (32.8 months) compared to NRAS (21.0 months) and wild-type patients (23.0 months). For ipilimumab-nivolumab treated patients, median OS was also significantly higher (p < 0.001) for BRAF mutated patients (36.5 months) than for NRAS mutated patients (11.8 months) and wild-type patients (16.1 months). After adjustment for potential confounders, the presence of a BRAF mutation remained associated with lower PFS in the anti-PD-1 treatment cohort and better OS in both treatment cohorts. Higher age, higher ECOG score, elevated LDH levels, liver metastases and brain metastases were associated with worse survival. Conclusions: PFS in first-line PD-1 was significantly higher for double wild-type patients than for BRAF mutant and NRAS mutant patients. PFS in ipilimumab-nivolumab treated patients did not significantly differ between BRAF mutant, NRAS mutant and double wild-type patients. OS was significantly higher for BRAF mutant patients in both treatment strata, which is probably the result of the subsequent BRAF/MEK-inhibition treatment option in this group.

Outcomes after retreatment with MAPK inhibitors and immune checkpoint inhibitors in melanoma patients

2021 ◽  
Author(s):  
Oana D Persa ◽  
Cornelia Mauch
Keyword(s):  
Disease Control ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Univariate Analysis ◽  
Progression Free Survival ◽  
Advanced Melanoma ◽  
Disease Control Rate ◽  
Unknown Primary ◽  
Free Survival ◽  
Mapk Inhibitors

Background: When patients with advanced melanoma progress after MAPK inhibitor (MAPKI) and immune checkpoint inhibitor (ICI) treatment, they can either undergo chemotherapy or rechallenge with previously used treatments. Methods: The outcomes of 48 patients retreated with MAPKIs and 50 patients retreated with ICIs following progression were retrospectively analyzed. Results: Upon retreatment with MAPKIs, the disease control rate was 60%. Univariate analysis of possible risk factors associated with short progression-free survival upon MAPKI treatment showed elevated lactate dehydrogenase to be associated with decreased progression-free survival. Disease control rate after ICI retreatment was 24%. Melanoma of unknown primary was associated with prolonged progression-free survival upon ICI retreatment. Conclusion: Retreatment with MAPKIs or ICIs is a feasible option for patients with advanced melanoma.

scholarly journals Atypical RAS Mutations in Metastatic Colorectal Cancer

2019 ◽  
pp. 1-11
Author(s):  
Filippo Pietrantonio ◽  
Rona Yaeger ◽  
Alexa B. Schrock ◽  
Giovanni Randon ◽  
Sandra Romero-Cordoba ◽  
...  
Keyword(s):  
Microsatellite Instability ◽  
Cancer Genomics ◽  
Medical Center ◽  
Molecular Data ◽  
Braf V600e ◽  
Cancer Center ◽  
Primary Resistance ◽  
Ras Mutations ◽  
Molecular Features ◽  
Exonuclease Domain

PURPOSE To describe the clinical and molecular features of metastatic colorectal cancers (mCRCs) bearing uncommon atypical RAS (At- RAS) mutations at codons other than 12, 13, 59, 61, 117, and 146. MATERIALS AND METHODS By exploiting five next-generation sequencing sources (Italian collaboration, Memorial Sloan Kettering Cancer Center, Samsung Medical Center, the Biomarker Research for Anti-EGFR Monoclonal Antibodies by Comprehensive Cancer Genomics (BREAC) study, and the Foundation Medicine database), we retrieved 175 At- RAS mutated cases. Molecular data were obtained from 163 samples from Memorial Sloan Kettering Cancer Center and the Foundation Medicine database. Clinical data were available for 27 At- RAS–positive and 467 negative cases from the Italian collaboration, Memorial Sloan Kettering Cancer Center, Samsung Medical Center, and the BREAC study. RESULTS At- RAS mutations were identified in 163 (0.9%) of 18,270 mCRCs. Among 133 with evaluable microsatellite instability status, 11 (8%) were microsatellite instability high. POLE exonuclease domain mutations had higher frequency (7%) than expected and were found only in microsatellite-stable tumors with high tumor mutational burden (TMB). Overall, 17% (28 of 163) of At- RAS cases had TMB greater than 20 mutations/Mb. Co-occurring typical RAS/BRAF V600E mutations and NF1 mutations, presumed to cause RAS activation, were found in 30% and 12% of samples, respectively (up to 43% and 50%, respectively, in TMB-high samples). Patients with RAS/BRAF wild-type mCRC achieved a median overall survival (OS) of 42.1 months, whereas those harboring isolated At- RAS, typical RAS, or BRAF V600E mutations showed a median OS of 32.3, 30.0, and 17.9 months, respectively ( P < .001). No significant OS difference ( P = .240) was found between patients with At- RAS versus typical RAS-mutated mCRC. Only one of six patients evaluable for primary resistance to anti–epidermal growth factor receptors achieved tumor response. CONCLUSION At- RAS mutations may be a marker for RAS pathway activation and can be associated with high co-occurrence of POLE exonuclease domain mutations.

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