Validation of the Combined Biomarker for Prediction of Response to Checkpoint Inhibitor in Patients with Advanced Cancer

Although immune checkpoint inhibitors can induce durable responses in patients with multiple types of advanced cancer, only a limited number of patients have a known reliable biomarker. This study aimed to validate the IMmunotherapy Against GastrIc Cancer (IMAGiC) model, which was developed based on a previous study of four-gene and PD-L1 level, to predict immunotherapy response. We developed a clinical assay for formalin-fixed paraffin-embedded samples using quantitative real-time polymerase chain reaction to measure the expression level of the previously published four-gene set. The predictive performance was validated in a cohort of 89 patients with several advanced tumor types. The IMAGiC score was derived from tumor samples of 89 patients consisting of eight cancer types, and 73 out of 89 patients available for clinical response were analyzed with clinicopathological factors. The IMAGiC group (responder vs. non-responder) was determined with a specific value of the IMAGiC score as a cutoff, which was set by log-rank statistics for progression-free survival (PFS) divided the patients into 56 (76.7%) non-responders and 17 (23.3%) responders. Clinical responders (complete response/partial response) were higher in the IMAGiC responder group than in the non-responder group (70.6 vs. 21.4%). The median PFS of the IMAGiC responder group and non-responder was 20.8 months (95% CI 9.1-not reached) and 6.7 months (95% CI 4.9–11.1, p = 0.007), respectively. Among the 17 IMAGiC responders, 11 patients had tumor mutation burden-low and microsatellite-stable tumors. This study validated a predictive model based on a four-gene expression signature. Along with conventional biomarkers, our model could be useful for predicting response to immunotherapy in patients with advanced cancer.

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Cell cycle and apoptosis regulatory protein (CARP)-1 expression in neuroblastoma.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.9578 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 9578-9578

Author(s):

Santosh S. Hanmod ◽

Samantha Siegel ◽

James Hatfield ◽

Edi Levi ◽

Marwan Zidan ◽

...

Keyword(s):

Small Sample Size ◽

Regulatory Protein ◽

Tumor Biology ◽

Progression Free Survival ◽

Small Sample ◽

Immune Histochemistry ◽

Formalin Fixed Paraffin ◽

Number Of Patients ◽

Significant Difference ◽

Formalin Fixed Paraffin Embedded

9578 Background: Neuroblastoma (NB) is the most common extra-cranial solid tumor in children. The prognosis for patients with high risk NB is still poor. Study of additional prognostic factors will enhance current understanding of the tumor biology and risk stratification. CARP-1 is a recently identified molecule mediating apoptosis signaling by agents like doxorubicin and etoposide. Since these agents are used in the front line treatment of NB, we tested whether CARP-1 expression could be another prognostic factor in NB. Methods: CARP-1 expression was examined by Western blot in a pair of NB cell lines, SK-N-SH and SK-N-SH Dox. We reviewed medical records of patients with NB at Children’s Hospital of Michigan from 2000-2009 and examined CARP-1 expression by immune-histochemistry in the archived, formalin fixed paraffin embedded NB tissues. CARP-1 expression was recorded as positive or negative. Correlation of CARP-1 expression and progression free survival (PFS) was calculated. Results: CARP-1 expression was detected in SK-N-SH but not SK-N-SH Dox, a doxorubicin-resistant derivative of SK-N-SH, suggesting that resistance to doxorubicin is associated with decreased level of CARP-1 expression in NB cells. Of the 30 cases studied, 53 % (16/30) expressed CARP-1. There was no significant difference in N-myc amplification status (13% vs.14%, p=0.3), or proportion of unfavorable Shimada histology (60% vs. 64%, p=0.5) between CARP-1 positive vs. negative groups. Twenty three percent (7/22) patients progressed or relapsed, including 2/16 (13%) in CARP-1 positive group vs. 5/14 (36%) in CARP-1 negative group (p=0.1). There was no significant difference in the PFS at 1 year (94% vs.79%, p=0.2) and 3 year (86% vs.71%, p=0.2) between CARP-1 positive vs. negative groups. Conclusions: CARP-1 expression was decreased in doxorubicin resistant NB cell line. CARP-1 expression was detected in approximately half (53%) of NB tumors. Patients with NB who expressed CARP-1 showed trend towards better 1- & 3-year PFS as compared to those who did not express CARP-1, however, the results are not statistically significant which could be due to the small sample size. Further study with a larger number of patients is warranted to clarify these findings.

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Immunotherapy discontinuation and outcome: A multicenter real-life experience.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e14075 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e14075-e14075

Author(s):

Maria Bassanelli ◽

Diana Giannarelli ◽

Maria RITA Migliorino ◽

Marco Russano ◽

Alain Gelibter ◽

...

Keyword(s):

Advanced Cancer ◽

Progressive Disease ◽

Life Experience ◽

Checkpoint Inhibitors ◽

Real Life ◽

Progression Free Survival ◽

Complete Response ◽

Response To Treatment ◽

Best Response ◽

Programmed Death

e14075 Background: Unlike chemotherapy, the optimum treatment duration with Immune checkpoint inhibitors (ICIs) is not clearly established. The aim of this study was to assess the outcome of patients (pts) who discontinued immune-based therapies for any reason except progressive disease. Methods: We conducted an observational, retrospective analysis of 46 consecutive pts with advanced cancer who received ICIs as clinically indicated, at eight Italian institutions. Tumor response to treatment was defined according to RECIST. Median overall survival (OS) and the 95% confidence interval (CI) were estimated with the Kaplan -Meier method. Results: 46 pts (median age 68 years [range 41-86]; male: 65.2%) with advanced cancer (n.39 non-small-cell lung cancer, n.15 renal cell carcinoma and n.2 melanoma) were treated with ICIs: 44 pts received programmed death 1 (PD-1) inhibitors (n.31 nivolumab, n.13 pembrolizumab) and 2 pts programmed death ligand 1 (PD-L1) (n.1 durvalumab, n.1 atezolizumab). A median of 8 cycles were administered [range 1 to 52]. 36 pts discontinued ICIs due to toxicities (diarrhoea, pneumonitis, hepatotoxicity) and 10 pts for reasons non immune-related. The median progression free survival (PFS) from the beginning of ICIs was 12.4 months (mo) [95% CI: 8.2-16.6] and the median OS was 20.0 mo (95% CI: 11.8-28.2). Median PFS from discontinuation of therapy was 5.0 mo [95% CI: 2.7-7.3] and median OS was 16.1 mo (95% CI: 5.4-26.8). Best response achieved according RECIST criteria were: 1 complete response (CR), 18 partial response, 21 stable disease (SD), 2 progressive disease (PR) and 3 non evaluable (NE). During interruption of ICIs 1 pts achieved a PR. Conclusions: This study shows the activity of ICIs, in terms of outcome and durable immune-response, in pts with advanced cancer even after treatment discontinuation.

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Analysis of consensus molecular subtypes (CMS) classification in the TRICOLORE trial: A randomized phase III trial of S-1 and irinotecan (IRI) plus bevacizumab (Bmab) versus mFOLFOX6 or CapeOX plus Bmab as first-line treatment for metastatic colorectal cancer (mCRC).

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.4_suppl.169 ◽

2020 ◽

Vol 38 (4_suppl) ◽

pp. 169-169

Author(s):

Satoshi Yuki ◽

Makio Gamoh ◽

Tadamichi Denda ◽

Atsuo Takashima ◽

Shin Takahashi ◽

...

Keyword(s):

Predictive Factor ◽

Progression Free Survival ◽

Phase Iii ◽

Line Treatment ◽

First Line ◽

Formalin Fixed Paraffin ◽

Number Of Patients ◽

Ffpe Samples ◽

Formalin Fixed Paraffin Embedded ◽

First Line Treatment

169 Background: The TRICOLORE trial previously demonstrated that S-1+IRI+Bmab (Arm B) was non-inferior to mFOLFOX6/CapeOX+Bmab (Arm A) in terms of progression-free survival (PFS) as first-line treatment for mCRC, irrespective of RAS status. CMS was reported to be a prognostic factor for mCRC. Previously, it was reported that the CMS could be a predictive factor for the efficacy of oxaliplatin (OX) and IRI (Okita A, et al. Oncotarget. 2018). In this exploratory study of TRICOLORE trial, we examined if the CMS could be a predictive factor of OX and IRI regimen. Methods: We collected formalin-fixed paraffin-embedded (FFPE) primary tumor tissues and performed gene expression analysis by microarray. The subtype of CMS was determined by the CMS classifier (Guinney et al. Nature Med. 2015). PFS and overall survival (OS) were compared between arm A and B in each subtypes of CMS. Results: Total of 308 FFPE samples from 487 cases who were enrolled in the TRICOLORE study were collected. Number of patients classified into CMS1 to CMS4 were 47, 72, 99 and 90, respectively. Similar to the previous reports, the proportion of RAS mutant cases was highest in CMS3 and the most of BRAF mutant cases were classified into CMS1. The median PFS (mPFS) of arm A and B were almost same in CMS2 (16.1m vs. 17.6m, HR = 1.10, p = 0.79) and CMS3 (10.6 vs. 11.4, HR = 0.95, p = 0.81). In CMS1, mPFS of arm A was worse than that of arm B, although not statistically significant (7.4m vs. 13.2m, HR = 0.73, p = 0.35). In CMS4, mPFS of arm B was better than that of arm A, although not statistically significant again (9.7m vs. 14.1m, HR = 0.72, p = 0.15). The median OS (mOS) of both arm in CMS2-CMS4 and arm B in CMS1 were good and were 29.0m or more. On the other hand, mOS of arm A in CMS1 (18.1m) was worse than the others. Conclusions: From these results, it was not concluded that CMS was a predictor of mFOLFOX6/CapeOX+Bmab and S-1+IRI+Bmab. However, mPFS and mOS of mFOLFOX6/CapeOX+Bmab in CMS1 were poor unlike other CMS subtypes, and these were consistent with a previous report. Whereas S-1+IRI+Bmab was effective in all subtypes of CMS. Clinical trial information: UMIN000007834.

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Treatment with therapeutic anticoagulation is not associated with immunotherapy response in advanced cancer patients

Journal of Translational Medicine ◽

10.1186/s12967-021-02712-w ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Paul Johannet ◽

Amelia Sawyers ◽

Nicholas Gulati ◽

Douglas Donnelly ◽

Samuel Kozloff ◽

...

Keyword(s):

Cancer Patients ◽

Advanced Cancer ◽

Immune Checkpoint ◽

Checkpoint Inhibitors ◽

Objective Response ◽

Progression Free Survival ◽

Immune Checkpoint Blockade ◽

Coagulation Cascade ◽

Advanced Cancer Patients ◽

Clinical Endpoints

Abstract Background Recent preclinical data suggest that there may be therapeutic synergy between immune checkpoint blockade and inhibition of the coagulation cascade. Here, we investigate whether patients who received immune checkpoint inhibitors (ICI) and were on concomitant anticoagulation (AC) experienced better treatment outcomes than individuals not on AC.Affiliation: Kindly confirm if corresponding authors affiliation is identified correctly.The corresponding author's affiliation is correct. Methods We studied a cohort of 728 advanced cancer patients who received 948 lines of ICI at NYU (2010–2020). Patients were classified based on whether they did (n = 120) or did not (n = 828) receive therapeutic AC at any point during their treatment with ICI. We investigated the relationship between AC status and multiple clinical endpoints including best overall response (BOR), objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), overall survival (OS), and the incidence of bleeding complications.Affiliations: Journal instruction requires a country for affiliations; however, this is missing in affiliations 1 to 5. Please verify if the provided country is correct and amend if necessary.The country is correct for all affiliations (1 - 5). Results Treatment with AC was not associated with significantly different BOR (P = 0.80), ORR (P =0.60), DCR (P =0.77), PFS (P = 0.59), or OS (P =0.64). Patients who received AC were significantly more likely to suffer a major or clinically relevant minor bleed (P = 0.05). Conclusion AC does not appear to impact the activity or efficacy of ICI in advanced cancer patients. On the basis of our findings, we caution that there is insufficient evidence to support prospectively evaluating the combination of AC and immunotherapy.

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Treatments after Immune Checkpoint Inhibitors in Patients with dMMR/MSI Metastatic Colorectal Cancer

Cancers ◽

10.3390/cancers14020406 ◽

2022 ◽

Vol 14 (2) ◽

pp. 406

Author(s):

Quang Loc Bui ◽

Léo Mas ◽

Antoine Hollebecque ◽

David Tougeron ◽

Christelle de la Fouchardière ◽

...

Keyword(s):

Colorectal Cancer ◽

Disease Control ◽

Metastatic Colorectal Cancer ◽

Checkpoint Inhibitors ◽

Progression Free Survival ◽

Immune Checkpoints ◽

Repair Deficiency ◽

Improved Outcomes ◽

Number Of Patients ◽

Tumor Types

Background: Several studies reported improved outcomes with conventional treatments (CT, i.e., chemotherapy ± targeted therapy) administered after immune checkpoints inhibitors (ICI) in certain tumor types. No data are available concerning patients (pts) with metastatic colorectal cancer (mCRC) harboring mismatch repair deficiency/microsatellite instability (dMMR/MSI). We aimed to assess the outcomes of dMMR/MSI mCRC pts receiving CT after ICI failure. Methods: We conducted a retrospective multicenter study investigating the outcomes of all dMMR/MSI mCRC pts who received post-ICI CT between 2015 and 2020. Results: 31 pts (male 61%, median age 56 years) were included. ICI was an anti-PD(L)1 monotherapy in 71% of pts, and 61% received >2 lines before post-ICI CT. The overall response rate and disease control rate were 13% and 45%, with a median progression-free survival (PFS) and overall survival of 2.9 and 7.4 months, respectively. No association of the outcomes with either ICI efficacy or anti-angiogenic agents was observed. Prolonged PFS (range 16.1–21.3 months) was observed in 4 pts (13%). Conclusions: Although conducted on a limited number of patients, our results do not support an association of previous ICI treatment with an enhanced efficacy of CT in dMMR/MSI mCRC. However, prolonged disease control was observed in several cases, suggesting that some pts might derive an unexpected benefit from post-ICI treatments.

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Tumor-associated immune cells and progression-free survival in advanced endometrial cancer (EC), results from the PHAEDRA trial (ANZGOG 1601).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.5584 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 5584-5584

Author(s):

Deborah Smith ◽

Kristy Robledo ◽

Sonia Yip ◽

Michelle Cummins ◽

Peey-Sei Kok ◽

...

Keyword(s):

Immune Cells ◽

Predictive Value ◽

Tumor Response ◽

External Validation ◽

Prognostic Significance ◽

Progression Free Survival ◽

Immune Biomarkers ◽

Formalin Fixed Paraffin ◽

Formalin Fixed Paraffin Embedded ◽

The Individual

5584 Background: Activity of durvalumab in patients with deficient mismatch repair (dMMR) advanced endometrial carcinoma (EC) was confirmed in the PHAEDRA trial (ANZGOG 1601). This study investigated the association between immune biomarkers and clinical outcomes in PHAEDRA. Methods: Formalin-fixed paraffin embedded sections immunohistochemically stained for PD-L1 using the Ventana platform, were with matched H&E slides scored independently by two pathologists according to the Ventana PD-L1 (SP263) algorithm for urothelial carcinoma (UC). Immune biomarkers assessed were PD-L1 staining of tumor cells (TCP) and immune cells (IC), and presence of tumor-associated immune cells (ICP). Results: Sixty-seven of the 71 patients had sufficient tumor for PD-L1 testing. AUC were 0.667, 0.726 and 0.644 for TCP, ICP and IC, respectively for predicting tumor response. Optimal cutpoints were TCP≥1%, ICP≥10% and IC≥35%. ICP≥10% achieved the highest sensitivity (53%) and specificity (82%) of the individual cutpoints. The optimal cutpoint algorithm was able to identify patients who would not respond, (sensitivity 88%, negative predictive value 92%), but had low specificity (48%) and positive predictive value (37%). Differences in PFS were found using ICP≥10% (logrank p = 0.01), compared to TCP (p = 0.25), IC (p = 0.48) and the UC algorithm (p = 0.08) (Figure 1). PFS was shorter in patients with pMMR than dMMR after adjusting for ICP (HR 2.99, 95%CI: 1.61-5.57, p < 0.001). Adjustment for MMR reduced the prognostic significance of ICP≥10% for PFS (HR 0.59, 95% CI: 0.28-1.23, p = 0.16). For OS, differences were seen for the UC algorithm (p = 0.02), but not ICP (p = 0.07), TCP (p = 0.18) or IC (p = 0.23). Similarly to PFS, adjustment for MMR reduced the prognostic significance of the UC algorithm for OS (HR: 0.53, 95% CI: 0.25-1.12, p = 0.10). Conclusions: In this exploratory analysis, ICP was more closely associated with tumor response and PFS than TCP or IC. ICP alone was better than the UC algorithm for predicting PFS. The optimum cutpoint algorithm was promising for identifying non-responders, but requires external validation. Clinical trial information: ACTRN12617000106336.

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Investigate the efficacy of immunotherapy for treatment of pancreatic adenocarcinoma (PDAC) with mismatch repair deficiency (dMMR).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.3_suppl.415 ◽

2021 ◽

Vol 39 (3_suppl) ◽

pp. 415-415

Author(s):

Arish Noor ◽

Luis E. Aguirre ◽

Kirsten Blue ◽

Trenton Avriett ◽

Estrella M. Carballido ◽

...

Keyword(s):

Pancreatic Adenocarcinoma ◽

Metastatic Disease ◽

Checkpoint Inhibitors ◽

Objective Response ◽

Locally Advanced ◽

Progression Free Survival ◽

Complete Response ◽

Median Number ◽

Cancer Center ◽

Duration Of Response

415 Background: Immune checkpoint inhibitors (ICI) have been approved in solid tumors with dMMR. However, only limited data are available for PDAC with dMMR given the rarity of dMMR in PDAC. We evaluated efficacy of ICIs in PDAC with dMMR. Methods: Retrospective clinical and pathologic data were collected for patients (pts) with pancreatic adenocarcinoma from May 2017 to June 2020 at Moffitt cancer center. Results: We identified 10 pts with dMMR PDAC. The median age was 64.5 years (range: 42-86) and 4 pts were male. 4 pts had resectable disease, 3 had locally advanced and 3 had metastatic disease at initial diagnosis. MSH6 deficiency (def) was found in 2 cases, PMS2 def in 2, MLH/PMS2 def in 5, and MSH2/MSH6 in 1. 7 pts were treated with ICIs. 3 pts had locally advanced and 4 had metastatic disease when they started ICIs. 5 received Pembrolizumab (pem), 1 received ipilimumab/ nivolumab (ipi/nivo), and 1 received pem then ipi/nivo after progressive disease (PD) on pem. The median number of prior lines of chemotherapy was 1 (range 0-2). 6 pts were evaluable, and 1 had rapid disease progression after 1 dose of pem. Among 6 evaluable pts, 3 had an objective response (1: complete response and 2: partial response), and 2 had stable disease (SD). Median progression-free survival was 8.2 mo, and median overall survival was not reached with median follow-up (FU) of 6.8 mo. The median duration of response was not reached with a median FU of 22.6 mo. The pt with CR remained disease-free for up to 22 months. The pt whose treatment was switched to ipi/nivo after PD on pem achieved SD > 4mo on ipi/nivo. While on immunotherapy, one patient with ipi/nivo developed immunotherapy associated rash requiring systemic steroids, and another on pem developed hypothyroidism requiring levothyroxine. Conclusions: This series suggest ICIs can provide durable clinical efficacy in pts with dMMR PDAC.

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Isatuximab plus carfilzomib and dexamethasone in east Asian patients with relapsed multiple myeloma: IKEMA subgroup analysis.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e20015 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e20015-e20015

Author(s):

Kihyun Kim ◽

Chang Ki Min ◽

Youngil Koh ◽

Kenichi Ishizawa ◽

Sung-Hyun Kim ◽

...

Keyword(s):

Multiple Myeloma ◽

Disease Progression ◽

Residual Disease ◽

East Asian ◽

Progression Free Survival ◽

Complete Response ◽

Efficacy And Safety ◽

Asian Patients ◽

Number Of Patients ◽

East Asian Patients

e20015 Background: The Phase 3 IKEMA study (NCT03275285) demonstrated that isatuximab (Isa) plus carfilzomib and dexamethasone (Kd) significantly improved progression-free survival (PFS) compared with Kd in patients (pts) with relapsed multiple myeloma (RMM) (hazard ratio [HR] 0.53; 99% confidence interval [CI] 0.32–0.89; P= 0.0007). We evaluated the efficacy and safety of Isa-Kd in the East Asian patients (19 Japanese, 27 Korean). Methods: RMM pts who received 1-3 prior lines of therapy were stratified to receive Isa-Kd or Kd. Isa-Kd arm received Isa (10 mg/kg intravenously) weekly for 4 weeks, then every 2 weeks. Both arms received K (20 mg/m2 days 1-2, 56 mg/m2 thereafter) twice-weekly for 3 of 4 weeks, and d (20 mg) twice-weekly. Treatment continued until disease progression or unacceptable adverse events (AE). The primary endpoint was prolongation of PFS. Key secondary endpoints included; very good partial response or better (≥VGPR), complete response (CR) rate and minimal residual disease negativity (MRD–) rate. Results: East Asian pts (25 Isa-Kd, 21 Kd) were randomized. Pt characteristics were similar in the East Asian subgroup compared with the intent to treat (ITT) population (N = 302). Median age (Isa-Kd 64.0 [range 45–83] years vs Kd 60.0 [range 33–73] years); median prior lines Isa-Kd 2.0 (range 1–3) vs Kd 1.0 (range 1–3); refractory to lenalidomide 16.0% Isa-Kd vs 47.6% Kd; refractory to PI 20.0% Isa-Kd vs 33.3% Kd; high-risk cytogenetics 48.0% Isa-Kd vs 42.9% Kd. After a median follow-up of 20.7 months, the addition of Isa to Kd improved ≥VGPR, CR and MRD– rates (Table). The HR 0.64 (95%CI: 0.231-1.764) for disease progression or death favored Isa-Kd. Grade ≥3 AEs were observed in 79.2% Isa-Kd vs 55.0% Kd pts, serious TEAEs in 45.8% Isa-Kd vs 50.0% Kd; TEAEs leading to treatment discontinuation were lower in the Isa-Kd group (4.2% Isa-Kd vs 10.0% Kd). Overall, 64.0% Isa-Kd vs 42.9% Kd pts were still receiving treatment. Conclusions: Efficacy and safety results of Isa-Kd in East Asian pts are consistent with the results of the overall IKEMA population, in which significantly better efficacy (PFS, CR, ≥VGPR and MRD– rate) was reported in favor of Isa-Kd without an increase in the number of patients with serious TEAEs or discontinuations. Isa-Kd is a potential treatment option for East Asian pts with RMM. Clinical trial information: NCT03275285. [Table: see text]

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Intrahepatic Cholangiocarcinoma: Genomic Heterogeneity Between Eastern and Western Patients

JCO Precision Oncology ◽

10.1200/po.18.00414 ◽

2020 ◽

pp. 557-569 ◽

Cited By ~ 5

Author(s):

Jingyu Cao ◽

Jing Hu ◽

Siqin Liu ◽

Funda Meric-Bernstam ◽

Reham Abdel-Wahab ◽

...

Keyword(s):

Dna Repair ◽

Intrahepatic Cholangiocarcinoma ◽

Checkpoint Inhibitors ◽

Asian Population ◽

Asian Patients ◽

Formalin Fixed Paraffin ◽

Mutation Burden ◽

Formalin Fixed Paraffin Embedded ◽

Comprehensive Genomic Profiling ◽

Ngs Data

PURPOSE Intrahepatic cholangiocarcinoma (IHCCA), a global health problem, is increasing in incidence and has differing etiologies worldwide. Next-generation sequencing (NGS) is rapidly being incorporated into the clinical management of biliary cancers. IHCCA is enriched with actionable mutations, and there are several promising targeted therapies under development. NGS data from Asia, where IHCCA is most prevalent, are limited. METHODS Comprehensive genomic profiling of formalin-fixed paraffin-embedded tumor tissue from 164 Asian and 283 Western patients with IHCCA was performed using NGS. We measured the distribution of DNA repair genetic aberrations (GAs) in IHCCA, along with actionable mutations. Also, we evaluated the association between DNA repair GAs and tumor mutation burden (TMB). Based on the TMB status, patients were distinguished into 3 levels: low (< 6 mut/Mb), intermediate (6-10 mut/Mb), and high (TMB-H; ≥ 10 mut/Mb). RESULTS Seventy-two percent of Asian patients had ≥ 1 actionable GA, with a significantly higher frequency in KMT2C , BRCA1/2, and DDR2 compared with Western patients ( P = .02, .003, and .003, respectively); 60.9% of Western patients had ≥ 1 actionable GA and higher frequency of CDKN2A/B and IDH1/2 GAs ( P = .0004 and < .001, respectively). GAs in nuclear factor kappa B pathway regulators and DNA repair genes occurred more frequently in Asian patients ( P = .006 and .001, respectively). There was a higher frequency of TMB-H in Asian compared with the Western cohort (12.2% v 5.9%; P = .07). CONCLUSION A higher burden of DNA repair mutations and frequency of patients with TMB-H in the Asian IHCCA cohort compared with the Western patients suggests a potential role for DNA repair and immune checkpoint inhibitors in the Asian population. Future clinical trials should account for this genetic heterogeneity.

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Frequency of genetic homologous recombination (HR) alterations in metastatic cutaneous melanoma.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e21033 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e21033-e21033

Author(s):

Kevin Kim ◽

Stanley P. L. Leong ◽

Mark I. Singer ◽

Brian M Parrett ◽

John Moretto ◽

...

Keyword(s):

Progression Free Survival ◽

Patient Characteristics ◽

Parp Inhibitors ◽

Mitotic Rate ◽

Formalin Fixed Paraffin ◽

Mutation Burden ◽

Formalin Fixed Paraffin Embedded ◽

Comprehensive Genomic Profiling ◽

Altered Gene ◽

Head And Neck Melanoma

e21033 Background: In various cancer types, cells with “BRCA-like” or HR mutations/alterations have been shown to be sensitive to PARP inhibitors in preclinical studies. In ovarian cancer, PARP inhibitors have shown improved response rate and progression-free survival in clinical studies. We investigated the frequency of HR mutations/alterations in melanoma. Methods: Comprehensive genomic profiling, (next-generation sequencing [NGS]) that included the entire coding sequence of 315 cancer-related genes was performed on formalin-fixed, paraffin-embedded tumor samples. The patient and tumor characteristics were obtained from electronic health records. Results: At our institution (CPMC), 59 patients underwent NGS analysis of melanoma specimens. Eighteen (30.5%) harbored a mutation in at least 1 of the HR genes in their tumor. The patient characteristics are: median age 69, male (83%), primary head and neck melanoma (61%), absence of ulceration at the primary site (86%) and mitotic rate >1 mm/m2 (86%). Tumor mutation burden was high in 12 (67%) patients and low in 1 (6%) patient. The most commonly altered gene was ARID2 (11.9%), followed by ARID1A, FANCA, ATM, BRCA1 (3.4% each). Three patients had multiple HR alterations: one with mutations in ARID1A, BRCA1 and MRE11A, one with mutations in ARID2 and ATM, and one with mutations in ARID2 and CHEK2. Among the 18 patients with HR mutation(s), concurrent NF1, NRAS, BRAF (V600), and KIT mutations were found in 7 (39%), 6 (33%), 5 (28%) and 1 (6%) patients, respectively. A larger dataset analyzed by Foundation Medicine (FM) (n=1,986) showed a similar pattern: The most common mutations/alterations were ARID2, followed by ARID1A, ATM, ATRX, BRCA2, ATR, BRCA1, BRIP1 and FANCA (Table). Conclusions: HR mutations / alterations are frequently observed in metastatic melanoma. Melanomas with these alterations may represent a unique subset of patients who could potentially benefit from PARP inhibitors. [Table: see text]

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