Tumor-Agnostic Biomarkers: Heed Caution, and Why Cell of Origin Still Matters

Since the very beginnings of cancer therapy with chemotherapy, tumors have been treated according to the organ or tissue of origin. The advent of precision medicine however, has recently led to growing promise for tumor-agnostic biomarkers for targeted therapies and immunotherapies, such as NTRK fusions. Despite this, prominent examples such as BRAF V600E mutations in melanoma compared to colorectal cancer, in which the site of tumor origin dramatically influences the efficacy of targeted therapies, heeds caution against disregarding the importance of cell of origin. Indeed, another illustrative example, is the almost complete absence outside of cancers originating from the lung of the classical activating EGFR mutations—exon 19 deletions and exon 21 L858R mutations. Consequently, an understanding of lineage dependency and lineage-survival oncogenes may still offer significant mechanistic insights into the malignant transformation of tumors to ultimately identify further therapeutic vulnerabilities.

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Systemic Therapy for Colorectal Cancer

10.2310/cgso.16189 ◽

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

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Impact of rapid multigene assays with short turnaround time (TAT) on the development of precision medicine for non-small cell lung cancer (NSCLC).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.9094 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 9094-9094

Author(s):

Shingo Matsumoto ◽

Takaya Ikeda ◽

Kiyotaka Yoh ◽

Akira Sugimoto ◽

Terufumi Kato ◽

...

Keyword(s):

Lung Cancer ◽

Clinical Trials ◽

Precision Medicine ◽

Targeted Therapies ◽

Advanced Nsclc ◽

Genetic Alterations ◽

Braf V600e ◽

Gene Testing ◽

Genomic Screening ◽

Nsclc Patients

9094 Background: A variety of oncogene drivers have been identified in NSCLC and molecularly-stratified precision medicine has led to improved survival in advanced NSCLC. Next-generation sequencing (NGS)-based testing is utilized to detect actionable gene alterations; however, the TAT of NGS is often too long to translate into clinical decision making. Thus, rapid multi-gene testing alternatives are needed. Methods: A lung cancer genomic screening project (LC-SCRUM-Asia) capturing clinical outcome was established in 2013 to identify patients with oncogene drivers and to support the development of novel targeted therapies. Since February 2013 to May 2019 (LC-SCRUM-Asia 1st-phase), single gene testing and/or a targeted NGS assay, Oncomine Comprehensive Assay (OCA), were used for the genomic screening. Since June 2019 to December 2020 (2nd-phase), a multi-gene PCR assay (Amoy 9-in-1 test) and a rapid NGS assay (Genexus/Oncomine Precision Assay [OPA]) were also implemented as rapid multi-gene testing. Results: A total of 10667 Japanese NSCLC patients, including 6826 in the 1st-phase and 3841 in the 2nd-phase, were enrolled in the LC-SCRUM-Asia. Success rate for OCA: 93%, for 9-in-1 test: 98%, for Genexus/OPA: 96%. Median TAT for OCA: 21 days, for 9-in-1 test: 3 days, for Genexus/OPA: 4 days. The frequencies of genetic alterations detected in the 1st-/2nd-phase were EGFR: 17/24%, KRAS: 15/16%, HER2 ex20ins: 4/3%, ALK fusions: 3/3%, RET fusions: 3/2%, ROS1 fusions: 3/2%, MET ex14skip: 2/2%, BRAF V600E: 1/1%, NRG1 fusions: 0/0.2% and NTRK3 fusions: 0.05/0.04%. Overall percent agreement of 9-in-1 test compared with OCA for EGFR/KRAS/HER2/BRAF/MET/ALK/ROS1/RET/NTRK3 alterations was 98%, and that of OPA compared with OCA was 95%. The rate of patients who received targeted therapies as 1st-line treatment was significantly elevated in the 2nd-phase compared with the 1st-phase (510/3841 [13%] vs. 567/6826 [8%], p < 0.001). Through the genomic screening, 1410 (37%) and 1269 (18%) candidate patients for clinical trials of KRAS, HER2, BRAF, MET, ALK, ROS1, RET or TRK-targeted drugs were identified in the 2nd-phase and in the 1st-phase, respectively. The rate of patients who were actually enrolled into the genotype-matched clinical trials were also significantly higher in the 2nd-phase than in the 1st-phase (222 [6%] vs. 186 [3%], p < 0.001). In 1st-line treatments for advanced NSCLC patients, the median progression-free survival was 8.5 months (95% CI, 7.7−9.4) in the 2nd-phase (n = 1839) versus 6.1 months (95% CI, 5.9−6.3) in the 1st-phase (n = 4262) (p < 0.001). Conclusions: Both the 9-in-1 test and Genexus/OPA had short TATs (3−4 days), high success rates (96−98%) and good concordance (95−98%) compared with another NGS assay (OCA). These rapid multi-gene assays highly contributed to enabling precision medicine and the development of targeted therapies for advanced NSCLC.

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Circulating tumor DNA dynamics, serial testing and evolution on treatment in 322 colorectal cancer patients.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.3566 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 3566-3566

Author(s):

Pashtoon Murtaza Kasi ◽

Saivaishnavi Kamatham ◽

Dorin Colibaseanu ◽

Amit Merchea ◽

Faisal Shahjehan ◽

...

Keyword(s):

Colorectal Cancer ◽

Selective Inhibition ◽

Circulating Tumor Dna ◽

Braf V600e ◽

Egfr Mutations ◽

Dna Dynamics ◽

Ongoing Research ◽

Serial Testing ◽

American Society ◽

Tumor Dna

3566 Background: According to the American Society of Clinical Oncology and College of American Pathologists (ASCO/CAP) joint review on circulating tumor DNA (ctDNA) issued in March 2018, widespread use of ctDNA assays in most patients with advanced cancer is still an area of ongoing research. However, multiple studies thereafter published and/or presented support its use in patients with metastatic colorectal cancer (CRC). This has led to several institutions adopting it as ‘clinical practice’. The aim of this study is to report on our institution’s adoption of ctDNA testing for every patient at the time of diagnosis and/or time of progression. Methods: We report on results of 322 CRC patients with 607 ctDNA tests at our center from January 2017 to February 2019 using a commercially available platform (Guardant360). Results: Among 322 patients of our cohort, a total of 607 ctDNA tests were done (Table). 127 (39.4%) of these tests were serial analyses. In the CRC patients who had serial testing, at progression, mechanisms of resistance included acquisition of KRAS, NRAS, EGFR mutations; and HER2- and MET-amplifications. The subclonal mutations were noted to disappear when the selective inhibition was stopped. This was seen in patients on targeted therapies/biologics rather than chemotherapy. This was of value in treatment modification, clinical trial selection and/or monitoring of disease progression in these patients. Conclusions: While ctDNA testing may not be ready for primetime in all advanced cancers, it is increasingly being adopted in practice for especially metastatic CRC. Of particular value is the serial ctDNA testing in the RAS/RAF wildtype subset and now BRAF V600E mutant CRC on anti-EGFR based therapies. [Table: see text]

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Precision Medicine for the Management of Therapy Refractory Colorectal Cancer

Journal of Personalized Medicine ◽

10.3390/jpm10040272 ◽

2020 ◽

Vol 10 (4) ◽

pp. 272

Author(s):

Hossein Taghizadeh ◽

Robert M. Mader ◽

Leonhard Müllauer ◽

Friedrich Erhart ◽

Alexandra Kautzky-Willer ◽

...

Keyword(s):

Colorectal Cancer ◽

Precision Medicine ◽

Targeted Therapies ◽

Targeted Treatment ◽

Treatment Recommendation ◽

Molecularly Targeted Therapy ◽

Time To Treatment Failure ◽

Heavily Pretreated ◽

Recommended Therapy ◽

Generation Sequencing

In this analysis, we examined the efficacy, feasibility, and limitations of molecular-based targeted therapies in heavily pretreated metastatic colorectal cancer (mCRC) patients after failure of all standard treatments. In this single-center, real-world retrospective analysis of our platform for precision medicine, we mapped the molecular profiles of 60 mCRC patients. Tumor samples of the patients were analyzed using next-generation sequencing panels of mutation hotspots, microsatellite instability testing, and immunohistochemistry. All profiles were reviewed by a multidisciplinary team to provide a targeted treatment recommendation after consensus discussion. In total, we detected 166 mutations in 53 patients. The five most frequently found mutations were TP53, KRAS, APC, PIK3CA, and PTEN. In 28 cases (47% of all patients), a molecularly targeted therapy could be recommended. Eventually, 12 patients (20%) received the recommended therapy. Six patients (10%) had a clinical benefit. The median time to treatment failure was 3.1 months. Our study demonstrates the feasibility and applicability of using targeted therapies in daily clinical practice for heavily pretreated mCRC patients. This could be used as a targeted treatment option in half of the patients.

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Systemic Therapy for Colorectal Cancer

10.2310/7800.16189 ◽

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

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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).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.3561 ◽

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]

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Prevalence of uncommon epidermal growth factor receptor (EGFR) alterations detected in circulating tumor DNA (ctDNA) of non-small cell lung cancer (NSCLC) patients from East Asia.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e21608 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e21608-e21608

Author(s):

Beung-Chul AHN ◽

Herbert H. F. Loong ◽

Oscar Siu-Hong Chan ◽

Michelle Mei Lin Lee ◽

Steven R. Olsen ◽

...

Keyword(s):

Lung Cancer ◽

East Asia ◽

East Asian ◽

Small Cell ◽

Braf V600e ◽

Egfr Mutations ◽

Synonymous Mutations ◽

Exon 20 ◽

Nsclc Patients ◽

Exon 19

e21608 Background: EGFR is the most commonly altered biomarker in East Asian NSCLC patients. Common driver mutations (L858R or exon 19 deletions (del)) are the focus of conventional hotspot testing which may overlook less common activating alterations such as single nucleotide variants (SNVs) in the tyrosine kinase or extracellular domain as well as exon 20 insertions (ins). We investigated the prevalence of uncommon EGFR mutations in ctDNA from NSCLC patients in East Asia tested by a commercially available comprehensive next generation sequencing (NGS) assay (Guardant360). This assay identifies SNVs, ins and del, fusions, and amplifications (amp), with complete exon sequencing of EGFR. Methods: Guardant360 test results from Hong Kong, Korea, Japan, Taiwan, and Southeast Asia were reviewed (cut-off December 2019). We identified cases with a diagnosis of “lung cancer,” excluding pure squamous, small cell, neuroendocrine, carcinoid and sarcomatoid histology. Patients enrolled in certain prospective clinical trials were excluded at the investigators’ request. Clinically relevant biomarkers were mutations in EGFR, BRAF (V600E), ERBB2, or KRAS; MET amp or exon 14 skipping; and ALK, ROS1, or RET fusions. Uncommon EGFR mutations were defined as those other than L858R, exon 19 del, or resistance SNV in codons 790-797; synonymous mutations and amp were excluded. Results: Plasma from 820 non-squamous NSCLC patients was tested. Samples came from 436 women and 384 men, median age 61 years. ctDNA was identified in samples from 701 patients (85% detection rate). Alterations in at least one clinically relevant gene were detected in 75% of the ctDNA positive cases: EGFR (54%), KRAS (8%), ALK (5%), ERBB2 (5%), RET (2%), MET (2%), BRAF (1%), ROS1 ( < 1%). Uncommon EGFR alterations were found in 115 samples (16%), with 63 (9%) potentially actionable (exon 19 ins (1); exon 20 ins (22); activating SNV (40), some with multiple mutations, including L718Q (6), L718V (5), G719A (5), L861Q (5), S768I (4), and others) and 52 (7%) variants of unknown significance. Uncommon EGFR mutations were the only clinically relevant biomarker in 53 samples (8%). Conclusions: Uncommon, potentially actionable EGFR mutations were found in 9% of plasma samples from East Asian NSCLC patients. In this clinical practice dataset, uncommon EGFR mutations were more prevalent than actionable biomarkers in other genes. These data support the use of NGS testing methods to identify NSCLC patients for appropriate EGFR-targeted therapy.

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