Personalized matched targeted therapy in advanced pancreatic cancer: a pilot cohort analysis.

Despite progress, 2-year pancreatic cancer survival remains dismal. We evaluated a biomarker-driven, combination/N-of-one strategy in 18 patients (advanced/metastatic pancreatic cancer) (from Molecular Tumor Board). Targeted agents administered/patient = 2.5 (median) (range, 1-4); first-line therapy (N = 5); second line, (N = 13). Comparing patients (high versus low degrees of matching) (matching score ≥50% versus <50%; reflecting number of alterations matched to targeted agents divided by number of pathogenic alterations), survival was significantly longer (hazard ratio [HR] 0.24 (95% confidence interval [CI], 0.078-0.76, P = 0.016); clinical benefit rates (CBR) (stable disease ≥6 months/partial/complete response) trended higher (45.5 vs 0.0%, P = 0.10); progression-free survival, HR, 95% CI, 0.36 (0.12-1.10) (p = 0.075). First versus ≥2nd-line therapy had higher CBRs (80.0 vs 7.7%, P = 0.008). No grade 3-4 toxicities occurred. The longest responder achieved partial remission (17.5 months) by co-targeting MEK and CDK4/6 alterations (chemotherapy-free). Therefore, genomically matched targeted agent combinations were active in these advanced pancreatic cancers. Larger prospective trials are warranted.

Precision medicine-based therapies in advanced colorectal cancer: The University of California San Diego Molecular Tumor Board experience.

Treatment for advanced colorectal cancer is often limited by complex molecular profiles, which promote resistance to systemic agents and targeted monotherapies. Recent studies suggest that a personalized, combinatorial approach of matching drugs to tumor alterations may be more effective. We implemented a precision medicine strategy by forming a Molecular Tumor Board (MTB), a multidisciplinary team of clinicians, scientists, bioinformaticians and geneticists. The MTB integrated molecular profiling information and patient characteristics to develop N-of-One treatments for 51 patients with advanced colorectal cancer. All patients had metastatic disease and 63% had received ≥ 3 prior therapy lines. Overall, 34/51 patients (67%) were matched to ≥ 1 drug recommended by the MTB based on individual tumor characteristics, whereas 17/51 (33%) patients received unmatched therapies. Patients who received matched therapy demonstrated significantly longer progression-free survival (hazard ratio [HR], 0.41; 95% confidence interval [CI], 0.21-0.81; P = 0.01) and a trend towards higher clinical benefit rates (41% vs. 18%, P = 0.058) (all multivariate) compared to patients receiving unmatched therapy. The MTB facilitated personalized matching of drugs to tumor characteristics, which was associated with improved progression-free survival in patients with advanced colorectal cancer.

Gastric Cancer, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology.

Gastric cancer is the third leading cause of cancer-related deaths worldwide. Over 95% of gastric cancers are adenocarcinomas, which are typically classified based on anatomic location and histologic type. Gastric cancer generally carries a poor prognosis because it is often diagnosed at an advanced stage. Systemic therapy can provide palliation, improved survival, and enhanced quality of life in patients with locally advanced or metastatic disease. The implementation of biomarker testing, especially analysis of HER2 status, microsatellite instability (MSI) status, and the expression of programmed death-ligand 1 (PD-L1), has had a significant impact on clinical practice and patient care. Targeted therapies including trastuzumab, nivolumab, and pembrolizumab have produced encouraging results in clinical trials for the treatment of patients with locally advanced or metastatic disease. Palliative management, which may include systemic therapy, chemoradiation, and/or best supportive care, is recommended for all patients with unresectable or metastatic cancer. Multidisciplinary team management is essential for all patients with localized gastric cancer. This selection from the NCCN Guidelines for Gastric Cancer focuses on the management of unresectable locally advanced, recurrent, or metastatic disease.

Establishment of Patient-Derived Succinate Dehydrogenase-Deficient Gastrointestinal Stromal Tumor Models for Predicting Therapeutic Response.

PURPOSE: Gastrointestinal stromal tumor (GIST) is the most common sarcoma of the gastrointestinal tract, with mutant succinate dehydrogenase (SDH) subunits (A-D) comprising less than 7.5% (i.e., 150-200/year) of new cases annually in the United States. Contrary to GISTs harboring KIT or PDGFRA mutations, SDH-mutant GISTs affect adolescents/young adults, often metastasize, and are frequently resistant to tyrosine kinase inhibitors (TKI). Lack of human models for any SDH-mutant tumors, including GIST, has limited molecular characterization and drug discovery. EXPERIMENTAL DESIGN: We describe methods for establishing novel patient-derived SDH-mutant (mSDH) GIST models and interrogated the efficacy of temozolomide on these tumor models in vitro and in clinical trials of patients with mSDH GIST. RESULTS: Molecular and metabolic characterization of our patient-derived mSDH GIST models revealed that these models recapitulate the transcriptional and metabolic hallmarks of parent tumors and SDH deficiency. We further demonstrate that temozolomide elicits DNA damage and apoptosis in our mSDH GIST models. Translating our in vitro discovery to the clinic, a cohort of patients with SDH-mutant GIST treated with temozolomide (n = 5) demonstrated a 40% objective response rate and 100% disease control rate, suggesting that temozolomide represents a promising therapy for this subset of GIST. CONCLUSIONS: We report the first methods to establish patient-derived mSDH tumor models, which can be readily employed for understanding patient-specific tumor biology and treatment strategies. We also demonstrate that temozolomide is effective in patients with mSDH GIST who are refractory to existing chemotherapeutic drugs (namely, TKIs) in clinic for GISTs, bringing a promising treatment option for these patients to clinic.See related commentary by Blakely et al., p. 3.

Molecular profiling of advanced malignancies guides first-line N-of-1 treatments in the I-PREDICT treatment-naïve study.

BACKGROUND: Malignancies are molecularly complex and become more resistant with each line of therapy. We hypothesized that offering matched, individualized combination therapies to patients with treatment-naïve, advanced cancers would be feasible and efficacious. Patients with newly diagnosed unresectable/metastatic, poor-prognosis cancers were enrolled in a cross-institutional prospective study. METHODS: A total of 145 patients were included in the study. Genomic profiling (tissue and/or circulating tumor DNA) was performed in all patients, and PD-L1 immunohistochemistry, tumor mutational burden, and microsatellite status assessment were performed in a subset of patients. We evaluated safety and outcomes: disease-control rate (stable disease for ≥ 6 months or partial or complete response), progression-free survival (PFS), and overall survival (OS). RESULTS: Seventy-six of 145 patients (52%) were treated, most commonly for non-colorectal gastrointestinal cancers, carcinomas of unknown primary, and hepatobiliary malignancies (53% women; median age, 63 years). The median number of deleterious genomic alterations per patient was 5 (range, 0-15). Fifty-four treated patients (71%) received ≥ 1 molecularly matched therapy, demonstrating the feasibility of administering molecularly matched therapy. The Matching Score, which reflects the percentage of targeted alterations, correlated linearly with progression-free survival (R2 = 0.92; P = 0.01), and high (≥ 60%) Matching Score was an independent predictor of improved disease control rate [OR 3.31 (95% CI 1.01-10.83), P = 0.048], PFS [HR 0.55 (0.28-1.07), P = 0.08], and OS [HR 0.42 (0.21-0.85), P = 0.02]. Serious adverse event rates were similar in the unmatched and matched groups. CONCLUSIONS: Personalized combination therapies targeting a majority of a patient's molecular alterations have antitumor activity as first-line treatment. These findings underscore the feasibility and importance of using tailored N-of-1 combination therapies early in the course of lethal malignancies. TRIAL REGISTRATION: I-PREDICT ( NCT02534675 ) was registered on August 25, 2015.

Neuroendocrine and Adrenal Tumors, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Neuroendocrine and Adrenal Gland Tumors focus on the diagnosis, treatment, and management of patients with neuroendocrine tumors (NETs), adrenal tumors, pheochromocytomas, paragangliomas, and multiple endocrine neoplasia. NETs are generally subclassified by site of origin, stage, and histologic characteristics. Appropriate diagnosis and treatment of NETs often involves collaboration between specialists in multiple disciplines, using specific biochemical, radiologic, and surgical methods. Specialists include pathologists, endocrinologists, radiologists (including nuclear medicine specialists), and medical, radiation, and surgical oncologists. These guidelines discuss the diagnosis and management of both sporadic and hereditary neuroendocrine and adrenal tumors and are intended to assist with clinical decision-making. This article is focused on the 2021 NCCN Guidelines principles of genetic risk assessment and counseling and recommendations for well-differentiated grade 3 NETs, poorly differentiated neuroendocrine carcinomas, adrenal tumors, pheochromocytomas, and paragangliomas.

SWI/SNF complex alterations as a biomarker of immunotherapy efficacy in pancreatic cancer.

BACKGROUNDImmune checkpoint inhibitors (ICIs) fail to demonstrate efficacy in pancreatic cancer. Recently, genomic biomarkers have been associated with response to ICIs: microsatellite instability high (MSI-H) and tumor mutation burden (TMB) > 10 mutations/Mb. Alterations in Switch/Sucrose Nonfermentable (SWI/SNF) chromatin remodeling genes may predispose to improved outcomes with immunotherapy. The current study examined a possible role for SWI/SNF complex abnormalities in pancreatic cancer responsiveness to ICIs.METHODSA database of 6831 cancer patients that had undergone next-generation sequencing (NGS) was filtered for advanced pancreatic cancer, SWI/SNF alterations, and outcomes depending on immunotherapy treatment.RESULTSNine patients had metastatic pancreatic adenocarcinoma harboring SWI/SNF chromatin remodeling gene alterations and had received ICIs: 7 had an ARID1A alteration (77%); 2, ARID1B (22%); 3, SMARCA4 (33%); 1, SMARCB1 (11%); and 1, PBRM1 (11%). Three patients possessed more than 1 SWI/SNF complex alteration. Only 3 tumors were microsatellite unstable. Eight of 9 patients (89%) achieved an objective response, including a complete remission, with the 2 longest responses ongoing at 33+ and 36+ months. Median progression-free and overall survival was 9 and 15 months, respectively. Responses occurred even in the presence of microsatellite stability, low TMB, and/or low PD-L1 expression.CONCLUSIONA small subset of patients with pancreatic cancer have genomic alterations in SWI/SNF chromatin remodeling components and appear to be responsive to ICIs, suggesting the need for prospective trials.TRIAL REGISTRATIONClinicalTrials.gov, NCT02478931.FUNDINGJoan and Irwin Jacobs Fund, NIH P30 CA023100 (RK) and LRP KYGF9753 (GPB), the Gershenson, Duarte, and anonymous patient families (GPB).

Location of Gastrointestinal Stromal Tumor (GIST) in the Stomach Predicts Tumor Mutation Profile and Drug Sensitivity.

PURPOSE: Gastrointestinal stromal tumors (GIST) commonly arise in different regions of the stomach and are driven by various mutations (most often in KIT, PDGFRA, and SDHx). We hypothesized that the anatomic location of gastric GIST is associated with unique genomic profiles and distinct driver mutations. EXPERIMENTAL DESIGN: We compared KIT versus non-KIT status with tumor location within the National Cancer Database (NCDB) for 2,418 patients with primary gastric GIST. Additionally, we compiled an international cohort (TransAtlantic GIST Collaborative, TAGC) of 236 patients and reviewed sequencing results, cross-sectional imaging, and operative reports. Subgroup analyses were performed for tumors located proximally versus distally. Risk factors for KIT versus non-KIT tumors were identified using multivariate regression analysis. A random forest machine learning model was then developed to determine feature importance. RESULTS: Within the NCDB cohort, non-KIT mutants dominated distal tumor locations (P < 0.03). Proximal GIST were almost exclusively KIT mutant (96%) in the TAGC cohort, whereas 100% of PDGFRA and SDH-mutant GIST occurred in the distal stomach. On multivariate regression analysis, tumor location was associated with KIT versus non-KIT mutations. Using random forest machine learning analysis, stomach location was the most important feature for predicting mutation status. CONCLUSIONS: We provide the first evidence that the mutational landscape of gastric GIST is related to tumor location. Proximal gastric GIST are overwhelmingly KIT mutant, irrespective of morphology or age, whereas distal tumors display non-KIT genomic diversity. Anatomic location of gastric GIST may therefore provide immediate guidance for clinical treatment decisions and selective confirmatory genomic testing when resources are limited.

Predictors and significance of histologic response to neoadjuvant therapy for gastric cancer.

BACKGROUND: Perioperative therapy is the standard-of-care for locally-advanced gastric cancer but many patients do not respond. There are currently no known factors that predict response to therapy. METHODS: This was a retrospective study aimed to evaluate treatment effect grade (TEG) in patients with locally advanced gastric cancer treated with neoadjuvant therapy and surgery at a single center. Ordinal logistic regression was performed to identify predictors of TEG, scaled from 0 to 3. RESULTS: Fifty patients were identified. The majority were male (n = 33) and 50% were Hispanic. The most common regimens given were: 5-fluorouracil/leucovorin, oxaliplatin, and docetaxel (n = 23, 46%), epirubicin, cis- or oxaliplatin, and 5-fluorouracil/leucovorin or Xeloda (n = 8, 16%), and 5-fluorouracil/leucovorin and oxaliplatin (n = 9, 18%). Twenty-seven patients (55%) had complete or partial response to therapy (TEG 0-2), and 23 patients (46%) had no response (TEG 3). Of numerous variables analyzed, only race and SRC histology were associated with TEG. TEG was associated with disease free, but not disease specific survival. CONCLUSIONS: In this cohort, 46% of patients had no histologic response to therapy. SRC histology, and possibly race, should be considered in determination of optimal multidisciplinary regimens and in amount of therapy to be given upfront, as patients with SRC histology and those of non-Asian race are less likely to respond to standard regimens.

Phase I Trial of Stereotactic Body Radiation Therapy Dose Escalation in Pancreatic Cancer.

PURPOSE: Stereotactic body radiation therapy (SBRT) has demonstrated encouraging local tumor control rates in the treatment of pancreatic cancer, yet we lack prospective clinical trials evaluating dose-escalation strategies among patients treated with 5-fraction SBRT. This phase 1 dose-escalation trial was conducted to determine the maximum tolerated dose of SBRT in patients with pancreatic cancer. METHODS AND MATERIALS: Thirty patients with pancreatic cancer were enrolled and treated with 40, 45, or 50 Gy SBRT in 5 fractions with doses determined using a time-to-event continual reassessment method trial design. Systemic therapy was permitted before and after SBRT, but not mandated by the study protocol. Toxicity was the primary study endpoint, and any grade ≥3 acute or late toxicity potentially attributable to SBRT was considered a dose-limiting toxicity. Secondary endpoints included local progression, distant progression, and overall survival. RESULTS: The median follow up from SBRT was 8.9 months (range, 1.7-62.6 months). Nineteen patients (63%) had locally advanced disease, 3 patients (10%) had metastatic disease, and 8 patients (27%) had medically unresectable disease. Three patients (10%) received 40 Gy, 16 patients (53%) received 45 Gy, and 11 patients (37%) received 50 Gy. Seven patients (23%) experienced grade ≤2 acute toxicity, and 2 patients (6.7%) experienced grade 4 to 5 late toxicity, both of which occurred in the 45 Gy group. Median survival time was 17.1 months from the time of diagnosis and 9.8 months from SBRT. The 1-year cumulative incidence of local progression was 14.2% (95% confidence interval, 4.2%-30%). CONCLUSIONS: This dose-escalation trial evaluated high-dose SBRT delivered in 5 fractions, and overall demonstrated favorable local control and survival, but was associated with nontrivial rates of severe late gastrointestinal toxicity potentially attributable to radiation. Further prospective studies are needed to define the safety and efficacy of high-dose SBRT in patients with pancreatic cancer.

Comprehensive genomic landscape and precision therapeutic approach in biliary tract cancers.

Biliary tract cancers have dismal prognoses even when cytotoxic chemotherapy is administered. There is an unmet need to develop precision treatment approaches using comprehensive genomic profiling. A total of 121 patients with biliary tract cancers were analyzed for circulating-tumor DNA (ctDNA) and/or tissue-based tumor DNA (tissue-DNA) using clinical-grade next-generation sequencing: 71 patients (59%) had ctDNA; 90 (74%), tissue-DNA; and 40 (33%), both. Efficacy of targeted therapeutic approaches was assessed based upon ctDNA and tissue-DNA. At least one characterized alteration was detected in 76% of patients (54/71) for ctDNA [median, 2 (range, 0-9)] and 100% (90/90) for tissue-DNA [median, 4 (range, 1-9)]. Most common alterations occurred in TP53 (38%), KRAS (28%), and PIK3CA (14%) for ctDNA vs TP53 (44%), CDKN2A/B (33%) and KRAS (29%) for tissue-DNA. In 40 patients who had both ctDNA and tissue-DNA sequencing, overall concordance was higher between ctDNA and metastatic site tissue-DNA than between ctDNA and primary tumor DNA (78% vs 65% for TP53, 100% vs 74% for KRAS and 100% vs 87% for PIK3CA [But not statistical significance]). Among 80 patients who received systemic treatment, the molecularly matched therapeutic regimens based on genomic profiling showed a significantly longer progression-free survival (hazard ratio [95%confidence interval], 0.60 [0.37-0.99]. P = .047 [multivariate]) and higher disease control rate (61% vs 35%, P = .04) than unmatched regimens. Evaluation of ctDNA and tissue-DNA is feasible in biliary tract cancers.

Real-world data from a molecular tumor board demonstrates improved outcomes with a precision N-of-One strategy.

Next-generation sequencing (NGS) can identify novel cancer targets. However, interpreting the molecular findings and accessing drugs/clinical trials is challenging. Furthermore, many tumors show resistance to monotherapies. To implement a precision strategy, we initiated a multidisciplinary (basic/translational/clinical investigators, bioinformaticians, geneticists, and physicians from multiple specialties) molecular tumor board (MTB), which included a project manager to facilitate obtaining clinical-grade biomarkers (blood/tissue NGS, specific immunohistochemistry/RNA expression including for immune-biomarkers, per physician discretion) and medication-acquisition specialists/clinical trial coordinators/navigators to assist with medication access. The MTB comprehensively reviewed patient characteristics to develop N-of-One treatments implemented by the treating physician's direction under the auspices of a master protocol. Overall, 265/429 therapy-evaluable patients (62%) were matched to ≥1 recommended drug. Eighty-six patients (20%) matched to all drugs recommended by MTB, including combinatorial approaches, while 38% received physician's choice regimen, generally with unmatched approach/low degree of matching. Our results show that patients who receive MTB-recommended regimens (versus physician choice) have significantly longer progression-free (PFS) and overall survival (OS), and are better matched to therapy. High (≥50%) versus low (<50%) Matching Score therapy (roughly reflecting therapy matched to ≥50% versus <50% of alterations) independently correlates with longer PFS (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.50-0.80; P < 0.001) and OS (HR, 0.67; 95% CI, 0.50-0.90; P = 0.007) and higher stable disease ≥6 months/partial/complete remission rate (52.1% versus 30.4% P < 0.001) (all multivariate). In conclusion, patients who receive MTB-based therapy are better matched to their genomic alterations, and the degree of matching is an independent predictor of improved oncologic outcomes including survival.

Prognostic implications of RAS alterations in diverse malignancies and impact of targeted therapies.

RAS alterations are often found in difficult-to-treat malignancies and are considered "undruggable." To better understand the clinical correlates and coaltered genes of RAS alterations, we used targeted next-generation sequencing (NGS) to analyze 1,937 patients with diverse cancers. Overall, 20.9% of cancers (405/1,937) harbored RAS alterations. Most RAS-altered cases had genomic coalterations (95.3%, median: 3, range: 0-51), often involving genes implicated in oncogenic signals: PI3K pathway (31.4% of 405 cases), cell cycle (31.1%), tyrosine kinase families (21.5%) and MAPK signaling (18.3%). Patients with RAS-altered versus wild-type RAS malignancies had significantly worse overall survival (OS; p = 0.02 [multivariate]), with KRAS alterations, in particular, showing shorter survival. Moreover, coalterations in both RAS and PI3K signaling or cell-cycle-associated genes correlated with worse OS (p = 0.004 and p < 0.0001, respectively [multivariate]). Among RAS-altered patients, MEK inhibitors alone did not impact progression-free survival (PFS), while matched targeted therapy against non-MAPK pathway coalterations alone showed a trend toward longer PFS (vs. patients who received unmatched therapy) (HR: 0.79, 95% CI: 0.61-1.03, p = 0.07). Three of nine patients (33%) given tailored combination therapies targeting both MAPK and non-MAPK pathways achieved objective responses. In conclusion, RAS alterations correlated with poor survival across cancers. The majority of RAS alterations were accompanied by coalterations impacting other oncogenic pathways. MEK inhibitors alone were ineffective against RAS-altered cancers while matched targeted therapy against coalterations alone correlated with a trend toward improved PFS. A subset of the small number of patients given MEK inhibitors plus tailored non-MAPK-targeting agents showed responses, suggesting that customized combinations warrant further investigation.

Clinical correlates of blood-derived circulating tumor DNA in pancreatic cancer.

BACKGROUND: Treatment outcomes for patients with advanced pancreatic ductal adenocarcinoma (PDAC) remain dismal. There are unmet needs for understanding the biologic basis of this malignancy using novel next-generation sequencing technologies. Herein, we investigated the clinical utility of circulating tumor DNA (ctDNA) (the liquid biopsy) in this malignancy. METHODS: ctDNA was analyzed in 112 patients with PDAC (54-73 genes) and tissue DNA in 66 patients (315 genes) (both clinical-grade next-generation sequencing). Number of alterations, %ctDNA, concordance between ctDNA and tissue DNA, and correlation of ctDNA results with survival were assessed. RESULTS: The most common genes altered in ctDNA were TP53 (46% of patients, N = 51) and KRAS (44%, N = 49). Median number of characterized ctDNA alterations per patient was 1 (range, 0-6), but patients with advanced PDAC had significantly higher numbers of ctDNA alterations than those with surgically resectable disease (median, 2 versus 0.5, P = 0.04). Overall, 75% (70/94) of advanced tumors had ≥ 1 ctDNA alteration. Concordance rate between ctDNA and tissue DNA alterations was 61% for TP53 and 52% for KRAS. Concordance for KRAS alterations between ctDNA and tissue DNA from metastatic sites was significantly higher than between ctDNA and primary tumor DNA (72% vs 39%, P = 0.01). Importantly, higher levels of total %ctDNA were an independent prognostic factor for worse survival (hazard ratio, 4.35; 95% confidence interval, 1.85-10.24 [multivariate, P = 0.001]). A patient with three ctDNA alterations affecting the MEK pathway (GNAS, KRAS, and NF1) attained a response to trametinib monotherapy ongoing at 6 months. CONCLUSIONS: Our findings showed that ctDNA often harbored unique alterations some of which may be targetable and that significantly greater numbers of ctDNA alterations occur in advanced versus resectable disease. Furthermore, higher ctDNA levels were a poor prognostic factor for survival.

Current management of succinate dehydrogenase-deficient gastrointestinal stromal tumors.

Gastrointestinal stromal tumors (GISTs) are increasingly recognized as having diverse biology. With the development of tyrosine kinase inhibitors molecularly matched to oncogenic KIT and PDGFRA mutations, GISTs have become a quintessential model for precision oncology. However, about 5-10% of GIST lack these driver mutations and are deficient in succinate dehydrogenase (SDH), an enzyme that converts succinate to fumarate. SDH deficiency leads to accumulation of succinate, an oncometabolite that promotes tumorigenesis. SDH-deficient GISTs are clinically unique in that they generally affect younger patients and are associated with GIST-paraganglioma hereditary syndrome, also known as Carney-Stratakis Syndrome. SDH-deficient GISTs are generally resistant to tyrosine-kinase inhibitors, the standard treatment for advanced or metastatic GIST. Thus, surgical resection is the mainstay of treatment for localized disease, but recurrence is common. Clinical trials are currently underway investigating systemic agents for treatment of advanced SDH-deficient GIST. However, further studies are warranted to improve our understanding of SDH-deficient GIST disease biology, natural history, surgical approaches, and novel therapeutics.

Genomic Profiling of Blood-Derived Circulating Tumor DNA from Patients with Colorectal Cancer: Implications for Response and Resistance to Targeted Therapeutics.

Molecular profiling of circulating tumor DNA (ctDNA) is a promising noninvasive tool. Here, next-generation sequencing (NGS) of blood-derived ctDNA was performed in patients with advanced colorectal cancer. We investigated ctDNA-derived genomic alterations, including potential actionability, concordance with tissue NGS, and serial dynamics in 78 patients with colorectal cancer using a clinical-grade NGS assay that detects single nucleotide variants (54-73 genes) and selected copy-number variants, fusions, and indels. Overall, 63 patients [80.8% (63/78)] harbored ctDNA alterations; 59 [75.6% (59/78)], ≥1 characterized alteration (variants of unknown significance excluded). All 59 patients had actionable alterations potentially targetable with FDA-approved drugs [on-label and/or off-label (N = 54) or with experimental drugs in clinical trials (additional five patients); University of California San Diego Molecular Tumor Board assessment]: 45, by OncoKB (http://oncokb.org/#/). The tissue and blood concordance rates for common specific alterations ranged from 62.3% to 86.9% (median = 5 months between tests). In serial samples from patients on anti-EGFR therapy, multiple emerging alterations in genes known to be involved in therapeutic resistance, including KRAS, NRAS, BRAF, EGFR, ERBB2, and MET were detected. In conclusion, over 80% of patients with stage IV colorectal cancer had detectable ctDNA, and the majority had potentially actionable alterations. Concordance between tissue and blood was between 62% and 87%, despite a median of 5 months between tests. Resistance alterations emerged on anti-EGFR therapy. Therefore, biopsy-free, noninvasive ctDNA analysis provides data relevant to the clinical setting. Importantly, sequential ctDNA analysis detects patterns of emerging resistance allowing for precision planning of future therapy.

Frequent rectal gastrointestinal stromal tumor recurrences in the imatinib era: Retrospective analysis of an International Patient Registry.

INTRODUCTION: Rectal gastrointestinal stromal tumor (GIST) is rare and comprises about 3% of GIST. METHODS: Registry data was collected by the Life Raft Group June 1976 to November 2017. All patients had a histologic GIST diagnosis. Demographic, clinicopathologic, and clinical outcome data were patient reported. Recurrence-free survival (RFS) was analyzed using the Kaplan-Meier method and Cox regression analysis. RESULTS: Of 1798 patients in the database, 48 had localized rectal GIST (2.7%). Patients were frequently male (58.3%) and non-Hispanic whites (58.3%). Median age at diagnosis was 52 years. Most patients (77%) were diagnosed in the imatinib era (2001 to current). Over half (54.2%) of the cohort had mutation testing and all profiled tumors possessed KIT mutations (exon 9: 7.7%, exon 11: 88.5%, and exon 13: 3.8%). Most evaluable patients (26/28; 92.9%) had high-risk disease (modified NIH criteria) and nearly all patients (95.8%) received imatinib. Median follow-up was 8.8 years (range, 0.3-30.7) and overall RFS was 8.0 years (95% CI, 2.9-13.1). Thirty-two percent (12/37) of patients in the post-imatinib era developed recurrent disease. Diagnosis in the imatinib era was associated with improved RFS (HR = 0.22, 95% CI, 0.08-0.62; P = .004) in the multivariable model. CONCLUSION: We find that disease recurrence remains prevalent in one-third of patients treated during the imatinib-era.

Esophageal and Esophagogastric Junction Cancers, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology.

Esophageal cancer is the sixth leading cause of cancer-related deaths worldwide. Squamous cell carcinoma is the most common histology in Eastern Europe and Asia, and adenocarcinoma is most common in North America and Western Europe. Surgery is a major component of treatment of locally advanced resectable esophageal and esophagogastric junction (EGJ) cancer, and randomized trials have shown that the addition of preoperative chemoradiation or perioperative chemotherapy to surgery significantly improves survival. Targeted therapies including trastuzumab, ramucirumab, and pembrolizumab have produced encouraging results in the treatment of patients with advanced or metastatic disease. Multidisciplinary team management is essential for all patients with esophageal and EGJ cancers. This selection from the NCCN Guidelines for Esophageal and Esophagogastric Junction Cancers focuses on recommendations for the management of locally advanced and metastatic adenocarcinoma of the esophagus and EGJ.

Revisiting Epidermal Growth Factor Receptor (EGFR) Amplification as a Target for Anti-EGFR Therapy: Analysis of Cell-Free Circulating Tumor DNA in Patients With Advanced Malignancies.

PURPOSE: To date, evidence for tissue epidermal growth factor receptor (EGFR) overexpression as a biomarker for anti-EGFR therapies has been weak. We investigated the genomic landscape of EGFR amplification in blood-derived cell-free tumor DNA (cfDNA) across diverse cancers and the role of anti-EGFR therapies in achieving response. METHODS: We assessed EGFR amplification status among 28,584 patients with malignancies evaluated by clinical-grade next-generation sequencing (NGS) of blood-derived cfDNA (54- to 73-gene panel). Furthermore, we curated the clinical characteristics of 1,434 patients at the University of California San Diego who had cfDNA testing by this NGS test. RESULTS: Overall, EGFR amplification was detected in cfDNA from 8.5% of patients (2,423 of 28,584), most commonly in colorectal (16.3% [458 of 2,807]), non-small-cell lung (9.0% [1,096 of 12,197]), and genitourinary cancers (8.1% [170 of 2,104]). Most patients had genomic coalterations (96.9% [95 of 98]), frequently involving genes affecting other tyrosine kinases (72.4% [71 of 98]), mitogen-activated protein kinase cascades (56.1% [55 of 98]), cell-cycle-associated signals (52.0% [51 of 98]), and the phosphoinositide 3-kinase pathway (35.7% [35 of 98]). EGFR amplification emerged in serial cfDNA after various anticancer therapies (n = 6), including checkpoint inhibitors (n = 4), suggesting a possible role for these amplifications in acquired resistance. Nine evaluable patients with EGFR amplification were treated with anti-EGFR-based regimens; five (55.6%) achieved partial responses, including three patients whose tissue NGS lacked EGFR amplification. CONCLUSION: EGFR amplification was detected in cfDNA among 8.5% of 28,584 diverse cancers. Most patients had coexisting alterations. Responses were observed in five of nine patients who received EGFR inhibitors. Incorporating EGFR inhibitors into the treatment regimens of patients harboring EGFR amplification in cfDNA merits additional study.

Genomic Assessment of Blood-Derived Circulating Tumor DNA in Patients With Colorectal Cancers: Correlation With Tissue Sequencing, Therapeutic Response, and Survival.

PURPOSE: Genomic alterations in blood-derived circulating tumor DNA (ctDNA) from patients with colorectal cancers were correlated with clinical outcomes. PATIENTS AND METHODS: Next-generation sequencing of ctDNA (54- to 73-gene panel) was performed in 94 patients with colorectal cancer. RESULTS: Most patients (96%) had metastatic or recurrent disease at the time of blood draw. The median number of nonsynonymous alterations per patient was three (range, zero to 30). The most frequently aberrant genes were TP53 (52.1% of patients), KRAS (34%), and APC (28.7%). Concordance between tissue and blood next-generation sequencing ranged from 63.2% (APC) to 85.5% (BRAF). Altogether, 74 patients (79%) had one or more nonsynonymous alterations, 69 (73%) had one or more potentially actionable alterations, and 61 (65%) had an alteration actionable by a drug approved by the US Food and Drug Administration (on or off label). Lung metastases correlated with improved survival from diagnosis in univariable analysis. ctDNA of 5% or more from blood tests as well as EGFR and ERBB2 (HER2) nonsynonymous alterations correlated with worse survival (but only ERBB2 remained significant in multivariable analysis). No two patients had identical molecular portfolios. Overall, 65% versus 31% of patients treated with matched (n = 17) versus unmatched therapy (n = 18) after ctDNA testing achieved stable disease for 6 months or more, partial response, or complete response (P = .045); progression-free survival, 6.1 versus 2.3 months (P = .08); and survival not reached versus 9.4 months (P = .146; all by multivariable analysis). CONCLUSION: Patients with colorectal cancer have heterogeneous ctDNA profiles, and most harbor potentially actionable ctDNA alterations. Matched therapy yielded higher rates of stable disease for 6 months or more, partial response, or complete response. ctDNA assessment may have clinical utility and merits further investigation.