Publications by authors named "Samuel J Klempner"

92 Publications

Use of Molecular Assays and Circulating Tumor DNA in Early Stage Colorectal Cancer: A Roundtable Discussion of the Gastrointestinal Cancer Therapy Expert Group (GICTEG).

Oncologist 2021 Mar 2. Epub 2021 Mar 2.

Huntsman Cancer Center at University of Utah, Salt Lake City, UT, USA.

The use of genomic testing is rapidly emerging as an important clinical tool, both for cancer diagnosis, and for guiding treatment decisions in a wide range of malignancies, including gastrointestinal (GI) cancers such as colorectal cancer (CRC). Advances in technologies such as polymerase chain reaction (PCR) and next-generation sequencing (NGS) methods have made it possible to non-invasively screen for CRC, for example, through the use of blood- or stool-based testing, with high specificity. Tests are also available that can provide prognostic information beyond traditional clinicopathologic factors such as tumor size, grade, and nodal status, which can enable clinicians to more accurately risk stratify patients for recurrence. Lastly, in the setting of resected CRC, tests are now available which can detect circulating tumor DNA (ctDNA) as a means for non-invasive minimal/molecular residual disease (MRD) monitoring, thereby potentially guiding the use of adjuvant chemotherapy and/or escalating or de-escalating therapy. The Gastrointestinal Cancer Therapy Expert Group (GICTEG) recently convened a virtual meeting to discuss current issues related to genomic testing in GI cancer, with the goal of providing guidance on the use of these tests for the practicing community oncologist, for whom GI cancer may be only one of many tumor types encountered. This article provides a summary of the discussion and highlights the key opinions of the GICTEG on this topic. IMPLICATIONS FOR PRACTICE: The Gastrointestinal Cancer Therapy Expert Group (GICTEG) seeks to provide practical guidance and opinion on the treatment of GI malignancies including colorectal cancer (CRC) for the practicing community oncologist, in situations where guidelines from established bodies such as the National Comprehensive Cancer Network (NCCN) and/or the American Society for Clinical Oncology (ASCO) may be less clear. In the present report, clinical guidance on the use of molecular assays for a range of clinical indications in CRC is presented, including the use of circulating tumor DNA (ctDNA) to detect minimal/molecular residual disease (MRD) in patients with successfully resected early stage CRC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/onco.13738DOI Listing
March 2021

LY3022855, an anti-colony stimulating factor-1 receptor (CSF-1R) monoclonal antibody, in patients with advanced solid tumors refractory to standard therapy: phase 1 dose-escalation trial.

Invest New Drugs 2021 Feb 23. Epub 2021 Feb 23.

Internal Medicine, Division of Medical Oncology, The Ohio State University Comprehensive Cancer Center, 1310D Lincoln Tower, 1800 Cannon Drive, Columbus, OH, 43210, USA.

Background Tumor-associated macrophages (TAMs) promote tumor growth, metastasis, and therapeutic resistance via colony-stimulating factor-1 (CSF-1), acting through CSF-1 receptor (CSF-1R) signaling. This phase 1 study determined the safety, tolerability, pharmacokinetics-pharmacodynamics, immunogenicity, and efficacy of the anti-CSF-1R antibody LY3022855 in solid tumors. Methods Patients with advanced solid tumors refractory to standard therapy were enrolled and treated in 2 dosing cohorts: weight-based (part A) and non-weight-based (part B). Part A patients were assigned to intravenous (IV) dose-escalation cohorts: 2.5 mg/kg once per week (QW), 0.3 mg/kg QW, 0.6 mg/kg QW, 1.25 mg/kg once every 2 weeks (Q2W) and 1.25 mg/kg QW doses of LY3022855. Non-weight-based doses in part B were 100 mg and 150 mg IV QW. Results Fifty-two patients (mean age 58.6 ± 10.4 years) were treated with ≥1 dose of LY3022855 (range: 4-6). Five dose-limiting toxicities (left ventricular dysfunction, anemia, pancreatitis, rhabdomyolysis, and acute kidney injury) occurred in 4 patients. The non-weight-based 100 mg QW dose was established as the RP2D. The most common treatment-emergent adverse events were increase in liver function variables, fatigue, nausea, vomiting, diarrhea, anorexia, pyrexia, increased lipase, amylase, and lactate dehydrogenase. Clearance decreased with increasing dose and weight-based dosing had minimal effect on pharmacokinetics. Serum CSF-1, and IL-34 levels increased at higher doses and more frequent dosing, whereas TAMs and CD14dimCD16bright levels decreased. Three patients achieved stable disease. No responses were seen. Conclusions LY3022855 was well tolerated and showed dose-dependent pharmacokinetics-pharmacodynamics and limited clinical activity in a heterogenous solid tumor population. ClinicalTrials.gov ID NCT01346358 (Registration Date: May 3, 2011).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10637-021-01084-8DOI Listing
February 2021

HIPEC for colorectal peritoneal metastases.

Lancet Oncol 2021 02 18;22(2):162-164. Epub 2021 Jan 18.

Mass General Cancer Center and Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA, USA. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1470-2045(20)30693-8DOI Listing
February 2021

Impact of Treatment Sequencing on Survival for Patients with Locally Advanced Gastric Cancer.

Ann Surg Oncol 2021 Jan 3. Epub 2021 Jan 3.

Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA.

Background: Data are limited concerning the survival outcomes of locally advanced gastric cancer patients according to the multimodality therapy (MMT) administered.

Methods: Single institution, retrospective analysis of 235 patients with locally advanced gastric cancer from 2001 to 2015. All patients met criteria for curative-intent surgery and chemotherapy ± radiation therapy. Treatment regimens were: (1) surgery first with adjuvant chemoradiation therapy (S + Adj); (2) perioperative chemotherapy + surgery (Periop); and (3) total neoadjuvant therapy followed by surgery (TNT + S).

Results: One hundred twenty-eight (60.0%) patients received S + Adj, 69 (26.8%) Periop, and 38 (13.2%) TNT + S. Of the 235 patients, 222 (94.5%) received surgery. All intended therapy was received by 81.6% of TNT + S, 44.5% of S + Adj, and 42.0% of Periop patients. MMT was significantly more likely to be completed by TNT + S patients (HR 6.67, p < 0.001). At a median follow-up of 37 months, survival rates on an intention-to-treat basis with TNT + S, Periop, and S + Adj were 52.6%, 59.4%, and 45.3%, respectively. Regimen and completion of MMT significantly affected overall mortality risk. Compared with Periop, TNT + S had similar mortality risk (hazard ratio [HR] 1.28, p = 0.421), whereas S + Adj had increased mortality risk (HR 1.64, p = 0.027).

Conclusions: The choice of treatment sequencing has a major impact on completion rates of multimodal therapy in patients with locally advanced gastric cancer. Less than 50% of patients treated with upfront surgery or perioperative chemotherapy receive all intended therapies. TNT has higher intended therapy completion rates and comparable survival compared with perioperative therapy in our data. Further prospective investigations of TNT are warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1245/s10434-020-09248-1DOI Listing
January 2021

Associations of baseline patient-reported outcomes with treatment outcomes in advanced gastrointestinal cancer.

Cancer 2021 Feb 10;127(4):619-627. Epub 2020 Nov 10.

Division of Hematology and Oncology, Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.

Background: Patient-reported outcomes (PROs) assessing quality of life (QOL) and symptom burden correlate with clinical outcomes in patients with cancer. However, to the authors' knowledge, data regarding associations between PROs and treatment response are lacking.

Methods: The authors prospectively approached consecutive patients with advanced gastrointestinal cancer who were initiating a new treatment. Prior to treatment, patients reported their QOL (Functional Assessment of Cancer Therapy-General [FACT-G], 4 subscales: Functional, Physical, Emotional, Social; higher scores indicate better QOL) and symptom burden (Edmonton Symptom Assessment System [ESAS], Patient Health Questionnaire-4 [PHQ-4]; higher scores represent greater symptoms). Regression models were used to examine associations of baseline PROs with treatment response (clinical benefit or progressive disease [PD] at time of first scan), healthcare utilization, and survival.

Results: From May 2019 to April 2020, a total of 112 patients with advanced gastrointestinal cancer were enrolled. For treatment response, 64.3% had CB and 35.7% had PD. Higher baseline ESAS-Physical (odds ratio, 1.04; P = .027) and lower FACT-G Functional (odds ratio, 0.92; P = .038) scores were associated with PD. Higher ESAS-Physical (hazard ratio [HR], 1.03; P = .044) and lower FACT-G Total (HR, 0.96; P = .005), FACT-G Physical (HR, 0.89; P < .001), and FACT-G Functional (HR, 0.87; P < .001) scores were associated with a greater hospitalization risk. Lower FACT-G Total (HR, 0.96; P = .009) and FACT-G Emotional (HR, 0.86; P = .012) scores as well as higher ESAS-Total (HR, 1.03; P = .014) and ESAS-Physical (HR, 1.04; P = .032) scores were associated with worse survival.

Conclusions: Baseline PROs are associated with treatment response in patients with advanced gastrointestinal cancer, namely physical symptoms and functional QOL, in addition to health care use and survival. The findings of the current study support the association between PROs and important clinical outcomes, including the novel finding of treatment response.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncr.33315DOI Listing
February 2021

Impact of palliative therapies in metastatic esophageal cancer patients not receiving chemotherapy.

World J Gastrointest Surg 2020 Sep;12(9):377-389

Department of Medicine, Division of Hematology and Oncology, Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, United States.

Background: Palliative therapy has been associated with improved overall survival (OS) in several tumor types. Not all patients with metastatic esophageal cancer receive palliative chemotherapy, and the roles of other palliative therapies in these patients are limited.

Aim: To investigate the impact of other palliative therapies in patients with metastatic esophageal cancer not receiving chemotherapy.

Methods: The National Cancer Database was used to identify patients between 2004-2015. Patients with M1 disease who declined chemotherapy and had known palliative therapy status [palliative therapies were defined as surgery, radiotherapy (RT), pain management, or any combination thereof] were included. Cases with unknown chemotherapy, RT, or nonprimary surgery status were excluded. Kaplan-Meier estimates of OS were calculated. Cox proportional hazards regression models were employed to examine factors influencing survival.

Results: Among 140234 esophageal cancer cases, we identified 1493 patients who did not receive chemotherapy and had complete data. Median age was 70 years, most (66.3%) had a Charlson Comorbidity Index (CCI) of 0, and 37.1% were treated at an academic center. The majority (72.7%) did not receive other palliative therapies. On both univariate and multivariable analyses, there was no difference in OS between those receiving other palliative therapy (median 2.83 mo, 95%CI: 2.53-3.12) no palliative therapy (2.37 no, 95%CI: 2.2-2.56; multivariable = 0.290). On univariate, but not multivariable analysis, treatment at an academic center was predictive of improved OS [Hazard ratio (HR) 0.90, 95%CI: 0.80-1.00; = 0.047]. On multivariable analysis, female sex (HR 0.81, 95%CI: 0.71-0.92) and non-black, other race compared to white race (HR 0.72, 95%CI: 0.56-0.93) were associated with reduced mortality, while South geographic region relative to West region (HR 1.23, 95%CI: 1.04-1.46) and CCI of 1 relative to CCI of 0 (HR 1.17, 95%CI: 1.03-1.32) were associated with increased mortality. Higher histologic grade and T-stage were also associated with worse OS ( < 0.05).

Conclusion: Palliative therapies other than chemotherapy conferred a numerically higher, but not statistically significant difference in OS among patients with metastatic esophageal cancer not receiving chemotherapy. Quality of life metrics, inpatient status, and subgroup analyses are important for examining the role of palliative therapies other than chemotherapy in metastatic esophageal cancer and future studies are warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4240/wjgs.v12.i9.377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7520571PMC
September 2020

A Space-Time Continuum for Immunotherapy Biomarkers in Gastroesophageal Cancer?

Clin Cancer Res 2020 Dec 6;26(24):6401-6403. Epub 2020 Oct 6.

City of Hope Comprehensive Cancer Center, Duarte, California.

In an annotated series of gastroesophageal adenocarcinomas differences in PD-L1 expression and tumor mutation burden occur between both paired contemporaneous primary and metastatic biopsies and pre/posttreatment samples. This work has implications for optimizing patient selection, serial testing, need for mechanistic understanding, and may underlie variable responses to checkpoint inhibitors in gastroesophageal cancers..
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-20-3389DOI Listing
December 2020

Revisiting MET: Clinical Characteristics and Treatment Outcomes of Patients with Locally Advanced or Metastatic, MET-Amplified Esophagogastric Cancers.

Oncologist 2020 11 12;25(11):e1691-e1700. Epub 2020 Sep 12.

Department of Radiation Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts, USA.

Background: Metastatic esophagogastric cancers (EGCs) have a poor prognosis with an approximately 5% 5-year survival. Additional treatment approaches are needed. c-MET gene-amplified tumors are an uncommon but potentially targetable subset of EGC. Clinical characteristics and outcomes were evaluated in patients with MET-amplified EGC and compared with those without MET amplification to facilitate identification of these patients and possible treatment approaches.

Patients And Methods: Patients with locally advanced or metastatic MET-amplified EGC at Massachusetts General Hospital (MGH) were identified using fluorescent in situ hybridization analysis, with a gene-to-control ratio of ≥2.2 defined as positive. Non-MET-amplified patients identified during the same time period who had undergone tumor genotyping and treatment at MGH were evaluated as a comparison group.

Results: We identified 233 patients evaluated for MET amplification from 2002 to 2019. MET amplification was seen in 28 (12%) patients versus 205 (88%) patients without amplification. Most MET-amplified tumors occurred in either the distal esophagus (n = 9; 32%) or gastroesophageal junction (n = 10; 36%). Of MET-amplified patients, 16 (57%) had a TP53 mutation, 5(18%) had HER2 co-amplification, 2 (7.0%) had EGFR co-amplification, and 1 (3.5%) had FGFR2 co-amplification. MET-amplified tumors more frequently had poorly differentiated histology (19/28, 68.0% vs. 66/205, 32%; p = .02). Progression-free survival to initial treatment was substantially shorter for all MET-amplified patients (5.6 vs. 8.8 months, p = .026) and for those with metastatic disease at presentation (4.0 vs. 7.6 months, p = .01). Overall, patients with MET amplification had shorter overall survival (19.3 vs. 24.6 months, p = .049). No difference in survival was seen between low MET-amplified tumors (≥2.2 and <25 MET copy number) compared with highly amplified tumors (≥25 MET copy number).

Conclusion: MET-amplified EGC represents a distinct clinical entity characterized by rapid progression and short survival. Ideally, the identification of these patients will provide opportunities to participate in clinical trials in an attempt to improve outcomes.

Implications For Practice: This article describes 233 patients who received MET amplification testing and reports (a) a positivity rate of 12%, similar to the rate of HER2 positivity in this data set; (b) the clinical characteristics of poorly differentiated tumors and nodal metastases; and (c) markedly shorter progression-free survival and overall survival in MET-amplified tumors. Favorable outcomes are reported for patients treated with MET inhibitors. Given the lack of published data in MET-amplified esophagogastric cancers and the urgent clinical importance of identifying patients with MET amplification for MET-directed therapy, this large series is a valuable addition to the literature and will have an impact on future practice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1634/theoncologist.2020-0274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648344PMC
November 2020

The Art of Oncology: COVID-19 Era.

Oncologist 2020 11 10;25(11):997-1000g. Epub 2020 Sep 10.

Division of Hematology and Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1634/theoncologist.2020-0512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405267PMC
November 2020

Genomic Alterations of NTRK, POLE, ERBB2, and Microsatellite Instability Status in Chinese Patients with Colorectal Cancer.

Oncologist 2020 11 10;25(11):e1671-e1680. Epub 2020 Aug 10.

Shu Lan (Hangzhou) Hospital, Hangzhou, People's Republic of China.

Background: The increasing molecular characterization of colorectal cancers (CRCs) has spurred the need to look beyond RAS, BRAF, and microsatellite instability (MSI). Genomic alterations, including ERBB2 amplifications and mutations, POLE mutations, MSI, and NTRK1-3 fusions, have emerged as targets for matched therapies. We sought to study a clinically annotated Chinese cohort of CRC subjected to genomic profiling to explore relative target frequencies.

Methods: Tumor and matched whole blood were collected from 609 Chinese patients with CRC. Extracted DNA was analyzed for all classes of genomic alterations across 450 cancer-related genes, including single-nucleotide variations (SNVs), short and long insertions and deletions (indels), copy number variations, and gene rearrangements. Next-generation sequencing-based computational algorithms also determined tumor mutational burden and MSI status.

Results: Alterations in TP53 (76%), APC (72%), and KRAS (46%) were common in Chinese patients with CRC. For the first time, the prevalence of NTRK gene fusion was observed to be around 7% in the MSI-high CRC cohort. Across the cohort, MSI was found in 9%, ERBB2 amplification in 3%, and POLE pathogenic mutation in 1.5% of patients. Such results mostly parallel frequencies observed in Western patients. However, POLE existed at a higher frequency and was associated with large tumor T-cell infiltration.

Conclusion: Comparing to the Western counterparts, POLE mutations were increased in our cohort. The prevalence of NTRK gene fusion was around 7% in the MSI-high CRC cohort. Increased adoption of molecular profiling in Asian patients is essential for the improvement of therapeutic outcomes.

Implications For Practice: The increasing use of genomic profiling assays in colorectal cancer (CRC) has allowed for the identification of a higher number of patient subsets benefiting from matched therapies. With an increase in the number of therapies, assays simultaneously evaluating all candidate biomarkers are critical. The results of this study provide an early support for the feasibility and utility of genomic profiling in Chinese patients with CRC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1634/theoncologist.2020-0356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648350PMC
November 2020

Endoscopic History and Provider Characteristics Influence Gastric Cancer Survival in Asian Americans.

Cancer Prev Res (Phila) 2020 Sep 19;13(9):773-782. Epub 2020 Jun 19.

Cedars-Sinai Medical Center, Los Angeles, California.

Gastric carcinoma (GC) disproportionately affects Asian Americans. We examined whether history of upper gastrointestinal (GI) endoscopy was associated with lower stage at GC diagnosis among Asian Americans and whether origin of providers influenced referral for endoscopy. We employed Surveillance Epidemiology and End Results-Medicare data on Asian Americans diagnosed with GC in 2004-2013 ( = 1,554). Stage distribution, GI conditions at diagnosis, and history of endoscopy were compared between Asian ethnic groups. Multivariate logistic regression adjusting for age, sex, poverty level, tumor location, and histology was used to examine the association of ethnicity and endoscopic history with stage I disease at diagnosis of GC. Koreans were more likely to be diagnosed with stage I, T1a GC and have prior history of endoscopy, compared with other Asian ethnicities (24% vs. 8% for stage I, T1a; 40% vs. 15% for endoscopy). Patients with primary care providers of concordant ethnic origin were more likely to have history of endoscopy. Asian American patients with GC with history of endoscopy were more likely to be diagnosed with GC at stage I disease (adjusted OR, 3.07; 95% confidence interval, 2.34-4.02). Compared with other Asian Americans, Koreans were diagnosed with GC at earlier stages owing to common history of endoscopy, which was more often undergone by patients with primary care providers of concordant ethnic origin. Overall, upper GI endoscopy was associated with early detection of GC in Asian Americans. It is well-established that Asian Americans in the United States are disproportionately affected by gastric cancer. In our study we found that Asian American patients treated by physicians of similar ethnic background are more likely to undergo upper GI endoscopy in the United States, leading to early detection of gastric cancer and longer survival. Given this, targeted endoscopic screening in Asian Americans should be considered for early detection of GC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1940-6207.CAPR-20-0058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483631PMC
September 2020

The anti-DKK1 antibody DKN-01 as an immunomodulatory combination partner for the treatment of cancer.

Expert Opin Investig Drugs 2020 Jul 25;29(7):639-644. Epub 2020 May 25.

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Alabama , Birmingham, AL, USA.

Introduction: The Wnt/beta-catenin pathway is a complex signaling pathway known to be dysregulated in several cancers; Dickkopf-1 (Dkk1) is an inhibitor of canonical Wnt signaling via negative feedback. Elevated Dkk1 is associated with a poor prognosis in several cancers, including gynecologic and gastroesophageal malignancies. This review focuses on the potential therapeutic benefit of targeting Dkk1 with the IgG4 monoclonal antibody, DKN-01.

Areas Covered: We highlight current treatment approaches for advanced gynecologic and esophageal malignancies highlighting the need for more effective therapies, specifically improved immune-modulating agents and combinations. Our discussion of DKN-01 addresses the rationale for targeting Dkk1, available safety, pharmacokinetic and efficacy data.

Expert Opinion: DKN-01 presents an interesting therapeutic consideration in advanced gynecologic and gastroesophageal malignancies. It has been especially promising in patients with high-Dkk1-expressing tumors or known Wnt mutations. We postulate that the complementary mechanisms, limited adverse effects and emerging biomarker data position DKN-01 as a promising agent for combination therapy in patients with advanced malignancies. Specifically, we believe this occurs through an immuno-modulatory effect, primarily acting through the innate arm of the immune system. This highlights the possibility for addressing innate immune resistance and expanding the portion of patients who may benefit, possibly in a biomarker-selected manner.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/13543784.2020.1769065DOI Listing
July 2020

Association Between Spatial Heterogeneity Within Nonmetastatic Gastroesophageal Adenocarcinomas and Survival.

JAMA Netw Open 2020 04 1;3(4):e203652. Epub 2020 Apr 1.

Department of Molecular and Cellular Biology, Beckman Research Institute of City of Hope, Duarte, California.

Importance: Intratumoral heterogeneity has been recognized as a significant barrier in successfully developing targetable biomarkers for gastroesophageal adenocarcinoma (GEA) and may affect neoadjuvant precision medicine approaches.

Objective: To describe intratumoral spatial heterogeneity of tumor cell populations in nonmetastatic GEA and its association with survival.

Design, Setting, And Participants: This case series retrospectively identified 41 patients with GEA who underwent up-front surgical resection at a tertiary referral cancer center from January 1, 1989, through December 31, 2013. Survival was calculated from date of surgery to date of death through June 1, 2017. Data were analyzed from June 2, 2017, to March 1, 2019.

Main Outcomes And Measures: Overall survival, intratumoral clonal composition determined by genomic single-nucleotide variation array and bioinformatic analysis, and intercellular tumoral distances determined by multiprobe fluorescence in situ hybridization.

Results: Among the 41 patients included in the analysis (22 men [54%]; mean [SD] age, 63 [12] years), a high proportion (19 [46%]) presented with tumors possessing high intratumoral heterogeneity. Kaplan-Meier analysis demonstrated that cases with an intratumoral clonal composition count of at least 2 exhibited worse survival compared with cases with a clonal composition count of 0 to 1 (univariate hazard ratio, 3.92; 95% CI, 1.27-12.08; P = .02). This finding remained significant on multivariate analysis controlling for stage, Lauren histologic subtype, receipt of adjuvant therapy, and age (multivariate hazard ratio, 4.55; 95% CI, 1.09-19.04; P = .04). Multiprobe fluorescence in situ hybridization demonstrated intratumoral clonal populations coexisting at submillimeter distances with differing relevant oncogenic copy number alterations, such as EGFR, JAK2, FGFR2, MET, CCND1, KRAS, MYC, PIK3CA, CD274, and PDCD1LG2.

Conclusions And Relevance: This study found that spatial intratumoral heterogeneity of oncogenic copy number alterations exists before metastatic dissemination, and increased heterogeneity was associated with worse outcomes in resected GEA. Baseline heterogeneity illustrates the challenges in GEA targeted therapy. Further study may offer insight into strategies on combinatorial and/or sequential targeted and immunotherapeutic approaches.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamanetworkopen.2020.3652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7186861PMC
April 2020

Lineage-Specific Epigenomic and Genomic Activation of Oncogene HNF4A Promotes Gastrointestinal Adenocarcinomas.

Cancer Res 2020 07 24;80(13):2722-2736. Epub 2020 Apr 24.

Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California.

Gastrointestinal adenocarcinomas (GIAC) of the tubular gastrointestinal (GI) tract including esophagus, stomach, colon, and rectum comprise most GI cancers and share a spectrum of genomic features. However, the unified epigenomic changes specific to GIAC are poorly characterized. Using 907 GIAC samples from The Cancer Genome Atlas, we applied mathematical algorithms to large-scale DNA methylome and transcriptome profiles to reconstruct transcription factor (TF) networks and identify a list of functionally hyperactive master regulator (MR) TF shared across different GIAC. The top candidate HNF4A exhibited prominent genomic and epigenomic activation in a GIAC-specific manner. A complex interplay between the HNF4A promoter and three distal enhancer elements was coordinated by GIAC-specific MRTF including ELF3, GATA4, GATA6, and KLF5. HNF4A also self-regulated its own promoter and enhancers. Functionally, HNF4A promoted cancer proliferation and survival by transcriptional activation of many downstream targets, including HNF1A and factors of interleukin signaling, in a lineage-specific manner. Overall, our study provides new insights into the GIAC-specific gene regulatory networks and identifies potential therapeutic strategies against these common cancers. SIGNIFICANCE: These findings show that GIAC-specific master regulatory transcription factors control HNF4A via three distal enhancers to promote GIAC cell proliferation and survival. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/13/2722/F1.large.jpg.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-20-0390DOI Listing
July 2020

A Pilot Study of Baseline Spatial Genomic Heterogeneity in Primary Gastric Cancers Using Multi-Region Endoscopic Sampling.

Front Oncol 2020 25;10:225. Epub 2020 Feb 25.

Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.

Intertumoral heterogeneity among actionable biomarkers including and has been observed to occur under therapeutic pressure in advanced gastric cancer. However, baseline intratumoral heterogeneity at diagnosis is understudied and may impact clinical outcomes. We sought to explore intratumoral heterogeneity in primary advanced gastric cancers via DNA sequencing from multi-region endoscopic sampling at diagnosis. Patients with newly diagnosed advanced gastric adenocarcinoma underwent endoscopic mapping and pre-determined 8-sector biopsy of the primary tumor with concurrent plasma cfDNA sampling. Biopsy samples were subjected to targeted next generation sequencing and plasma cfDNA was analyzed via a 28-gene cfDNA assay. Expectedly, we observed that the majority of genetic alterations were shared among multi-sector biopsies within the same gastric primary tumor. However, all samples contained private subclonal alterations between biopsy sectors, including actionable alterations in and . Cell free DNA analyses also exhibited both shared and non-shared alterations between mutations detected in cfDNA and tumor tissue biopsies confirming baseline intertumoral heterogeneity. This is the first dataset to confirm baseline intratumoral heterogeneity and confirms that multi-sector endoscopic biopsy is feasible and capable of capturing intratumoral heterogeneity among relevant genomic alterations in gastric cancer. Both multi-sector endoscopic biopsies and cfDNA analyses are complementary in capturing the diverse mutational landscape at disease presentation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2020.00225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052337PMC
February 2020

High-level FGFR2 amplification is associated with poor prognosis and Lower response to chemotherapy in gastric cancers.

Pathol Res Pract 2020 Apr 13;216(4):152878. Epub 2020 Feb 13.

Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. Electronic address:

Background: Recurrent FGFR2 amplification is observed in gastroesophageal cancers but clinical implications are unknown. We investigated the association of FGFR2 amplification with cytotoxic chemotherapy outcome in gastroesophageal cancer (GC) patients.

Methods: Between 2016 and 2018, we identified 1045 metastatic GC patients who received palliative fluoropyrimidine/platinum-based chemotherapy and underwent tumor genomic profiling at a tertiary hospital in Korea and two US cancer centers. We retrospectively identified FGFR2-amplified cases and abstracted clinicopathologic features and treatment outcomes. Cox proportional hazard regression model was used to evaluate the variables that demonstrated effects on progression free and overall survival PFS and OS. Descriptive statistics were used to correlate level of FGFR2 copy number amplification CNA and clinicopathological parameters.

Results: The incidence of FGFR2-amplified GC was 4.0 %. A total of 42 FGFR2-amplified GC patients were included and divided into high and lower FGFR2 amplification values. Fifteen patients had an FGFR2 CNA greater than 30, and 27 had a CNA of 30 or less. There was no significant differences between age, sex, tumor localization, Lauren classification, or tumor staging. After a median follow-up duration of 11.4 months, patients with high FGFR2 amplification had significantly poorer median PFS (3.2 vs. 4.8 months, hazard ratio (HR) 2.08, 95 % CI, 1.03-4.22, P = 0.042) and significantly shorter median OS (10.1 vs. 26.3 months, HR 2.99, 95 % CI = 1.05-8.49, P = 0.040) than the low FGFR2 amplification group.

Conclusion: Recurrent FGFR2 amplification was observed in roughly 4.0 % of GC patients. High FGFR2 amplification was significantly associated with poor progression free survival and overall survival in GC patients. Clinical studies of FGFR2-directed therapies are warranted and should consider stratification by FGFR2 CNA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.prp.2020.152878DOI Listing
April 2020

Impact of Postoperative Complication and Completion of Multimodality Therapy on Survival in Patients Undergoing Gastrectomy for Advanced Gastric Cancer.

J Am Coll Surg 2020 06 6;230(6):912-924. Epub 2020 Feb 6.

Department of Surgery, Boston, MA; Massachusetts General Hospital, and Harvard Medical School, Boston, MA. Electronic address:

Background: Postoperative complication (POC) adversely impacts long-term survival in patients with gastric cancer, perhaps due in part to lower rates for receipt of multimodality therapy (MMT). We sought to determine the impact of POC on MMT completion rates and overall survival (OS) in patients with locally advanced gastric cancer.

Study Design: We analyzed 206 patients with locally advanced gastric cancer undergoing curative-intent resection from 2001 to 2015. POCs were graded using Clavien-Dindo classification and survival outcomes were compared between groups.

Results: One hundred and twenty patients underwent operation followed by chemoradiation therapy, 58 received perioperative chemotherapy, and 28 received total neoadjuvant therapy (TNT). Minor (Clavien-Dindo grade I to II) and major (Clavien-Dindo grade III to IV) POC occurred in 72 (35.0%) and 39 (18.9%) patients, respectively. At median follow-up of 37 months, the 3-year OS of patients experiencing a major, minor, or no POC were 33.3%, 56.9%, and 62.1% (p = 0.023), respectively. In contrast, there was no difference in 3-year OS rates in patients experiencing POC if they completed all intended MMT. Non-TNT patients who experienced a major POC were less likely to complete MMT (hazard ratio 0.36, p = 0.017), and a major POC in these patients had a significant impact on OS (hazard ratio 2.76, p = 0.011), and it did not in patients who completed MMT (hazard ratio 1.58, p = 0.336).

Conclusions: Major POC adversely affects long-term survival after gastrectomy for gastric cancer, at least in part via lower completion rates of MMT. Treatment strategy designed to ensure the completion of MMT, such as TNT, might be preferable, particularly for patients at high risk for POCs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jamcollsurg.2019.12.038DOI Listing
June 2020

Can the Help Match the Hype? KRAS-Specific Inhibitors and Beyond.

Cancer Discov 2020 01;10(1):20-22

Divsion of Hematology-Oncology, Massachusetts General Hospital Cancer Center, Boston, Massachusetts.

Hallin and colleagues demonstrate the preclinical activity of the KRAS-specific inhibitor MRTX849 in a series of and studies with supporting pilot clinical efficacy. Variable responsiveness despite effective KRAS inhibition highlights both the promise and potential need for combinatorial strategies to optimally target KRAS-driven cancers..
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/2159-8290.CD-19-1255DOI Listing
January 2020

Receptor Tyrosine Kinase Fusions as an Actionable Resistance Mechanism to EGFR TKIs in EGFR-Mutant Non-Small-Cell Lung Cancer.

Trends Cancer 2019 11 29;5(11):677-692. Epub 2019 Oct 29.

University of California Irvine School of Medicine, Department of Medicine, Division of Hematology/Oncology, Chao Family Comprehensive Cancer Center, Orange, CA 92868, USA. Electronic address:

Tumor resistance to EGFR tyrosine kinase inhibitors (TKIs) occurs invariably, and receptor tyrosine kinase (RTK) fusions have emerged as rare but actionable resistance mechanisms. In 2015, the detection of RTK fusions as acquired resistance (AR) in two cases was first reported. Subsequently, a survey of FGFR3-TACC3 fusion and other RTK fusions from a large commercial genomic sequencing company database was published, followed by large-scale clinical trials of EGFR TKIs demonstrating the emergence of RTK fusions in AR. However, detailed examination of the AR RTK fusion landscape in non-small-cell lung cancer is lacking. Hence, we conducted a comprehensive review to categorize these fusion events by the generation of EGFR TKIs, the specific RTK fusions and their fusion partners, the founder EGFR mutations, and their methods of detection. To support the actionability and clinical significance of AR RTK fusions we present all available data demonstrating clinical benefit of concurrent dual blockade of the AR RTK fusion and the original EGFR mutation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.trecan.2019.09.008DOI Listing
November 2019

Sequence, Treat, Repeat: Addressing Resistance in EGFR-Mutant NSCLC.

J Thorac Oncol 2019 11;14(11):1875-1877

Massachusetts General Hospital Cancer Center, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtho.2019.07.014DOI Listing
November 2019

The Pan-Cancer Landscape of Coamplification of the Tyrosine Kinases KIT, KDR, and PDGFRA.

Oncologist 2020 01 11;25(1):e39-e47. Epub 2019 Oct 11.

Foundation Medicine, Inc., Cambridge, Massachusetts, USA.

Purpose: Amplifications of receptor tyrosine kinases (RTKS) are therapeutic targets in multiple tumor types (e.g. HER2 in breast cancer), and amplification of the chromosome 4 segment harboring the three RTKs KIT, PDGFRA, and KDR (4q12amp) may be similarly targetable. The presence of 4q12amp has been sporadically reported in small tumor specific series but a large-scale analysis is lacking. We assess the pan-cancer landscape of 4q12amp and provide early clinical support for the feasibility of targeting this amplicon.

Experimental Design: Tumor specimens from 132,872 patients with advanced cancer were assayed with hybrid capture based comprehensive genomic profiling which assays 186-315 genes for all classes of genomic alterations, including amplifications. Baseline demographic data were abstracted, and presence of 4q12amp was defined as 6 or more copies of KIT/KDR/PDGFRA. Concurrent alterations and treatment outcomes with matched therapies were explored in a subset of cases.

Results: Overall 0.65% of cases harbored 4q12amp at a median copy number of 10 (range 6-344). Among cancers with >100 cases in this series, glioblastomas, angiosarcomas, and osteosarcomas were enriched for 4q12amp at 4.7%, 4.8%, and 6.4%, respectively (all p < 0.001), giving an overall sarcoma (n = 6,885) incidence of 1.9%. Among 99 pulmonary adenocarcinoma cases harboring 4q12amp, 50 (50%) lacked any other known driver of NSLCC. Four index cases plus a previously reported case on treatment with empirical TKIs monotherapy had stable disease on average exceeding 20 months.

Conclusion: We define 4q12amp as a significant event across the pan-cancer landscape, comparable to known pan-cancer targets such as NTRK and microsatellite instability, with notable enrichment in several cancers such as osteosarcoma where standard treatment is limited. The responses to available TKIs observed in index cases strongly suggest 4q12amp is a druggable oncogenic target across cancers that warrants a focused drug development strategy.

Implications For Practice: Coamplification of the receptor tyrosine kinases (rtks) KIT/KDR/PDGFRA (4q12amp) is present broadly across cancers (0.65%), with enrichment in osteosarcoma and gliomas. Evidence for this amplicon having an oncogenic role is the mutual exclusivity of 4q12amp to other known drivers in 50% of pulmonary adenocarcinoma cases. Furthermore, preliminary clinical evidence for driver status comes from four index cases of patients empirically treated with commercially available tyrosine kinase inhibitors with activity against KIT/KDR/PDGFRA who had stable disease for 20 months on average. The sum of these lines of evidence suggests further clinical and preclinical investigation of 4q12amp is warranted as the possible basis for a pan-cancer drug development strategy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1634/theoncologist.2018-0528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6964135PMC
January 2020

Tumor Mutational Burden as a Predictive Biomarker for Response to Immune Checkpoint Inhibitors: A Review of Current Evidence.

Oncologist 2020 01 2;25(1):e147-e159. Epub 2019 Oct 2.

Foundation Medicine, Inc., Cambridge, Massachusetts, USA.

Treatment with immune checkpoint inhibitors (ICPIs) extends survival in a proportion of patients across multiple cancers. Tumor mutational burden (TMB)-the number of somatic mutations per DNA megabase (Mb)-has emerged as a proxy for neoantigen burden that is an independent biomarker associated with ICPI outcomes. Based on findings from recent studies, TMB can be reliably estimated using validated algorithms from next-generation sequencing assays that interrogate a sufficiently large subset of the exome as an alternative to whole-exome sequencing. Biological processes contributing to elevated TMB can result from exposure to cigarette smoke and ultraviolet radiation, from deleterious mutations in mismatch repair leading to microsatellite instability, or from mutations in the DNA repair machinery. A variety of clinical studies have shown that patients with higher TMB experience longer survival and greater response rates following treatment with ICPIs compared with those who have lower TMB levels; this includes a prospective randomized clinical trial that found a TMB threshold of ≥10 mutations per Mb to be predictive of longer progression-free survival in patients with non-small cell lung cancer. Multiple trials are underway to validate the predictive values of TMB across cancer types and in patients treated with other immunotherapies. Here we review the rationale, algorithm development methodology, and existing clinical data supporting the use of TMB as a predictive biomarker for treatment with ICPIs. We discuss emerging roles for TMB and its potential future value for stratifying patients according to their likelihood of ICPI treatment response. IMPLICATIONS FOR PRACTICE: Tumor mutational burden (TMB) is a newly established independent predictor of immune checkpoint inhibitor (ICPI) treatment outcome across multiple tumor types. Certain next-generation sequencing-based techniques allow TMB to be reliably estimated from a subset of the exome without the use of whole-exome sequencing, thus facilitating the adoption of TMB assessment in community oncology settings. Analyses of multiple clinical trials across several cancer types have demonstrated that TMB stratifies patients who are receiving ICPIs by response rate and survival. TMB, alongside other genomic biomarkers, may provide complementary information in selecting patients for ICPI-based therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1634/theoncologist.2019-0244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6964127PMC
January 2020

Efficacy of PD-1 Blockade in Refractory Microsatellite-Stable Colorectal Cancer With High Tumor Mutation Burden.

Clin Colorectal Cancer 2019 12 4;18(4):307-309. Epub 2019 Sep 4.

Division of Hematology and Oncology, Department of Internal Medicine, UC Davis Comprehensive Cancer Center, Sacramento, CA. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clcc.2019.08.001DOI Listing
December 2019

Checkpoint inhibition in advanced gastroesophageal cancer: clinical trial data, molecular subtyping, predictive biomarkers, and the potential of combination therapies.

Transl Gastroenterol Hepatol 2019 27;4:63. Epub 2019 Aug 27.

Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

The development of checkpoint inhibitors has redefined the treatment paradigm for advanced gastroesophageal cancer. While recent developments have improved clinical outcomes, the prognosis for the disease remains meager. In this review, we discuss the rationale and detail the results from recent phase I-III trials supporting the activity of PD-1 inhibitors. Specifically, we highlight the seminal clinical trials leading to the FDA approval of pembrolizumab for advanced gastroesophageal cancer. Finally, we review the current understanding and future considerations of molecular subtyping and predictive biomarkers to help guide therapy and the promise of combination therapy to further improve the efficacy of checkpoint inhibitors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21037/tgh.2019.08.04DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6737389PMC
August 2019

Master transcription factors form interconnected circuitry and orchestrate transcriptional networks in oesophageal adenocarcinoma.

Gut 2020 04 13;69(4):630-640. Epub 2019 Aug 13.

Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA.

Objective: While oesophageal squamous cell carcinoma remains infrequent in Western populations, the incidence of oesophageal adenocarcinoma (EAC) has increased sixfold to eightfold over the past four decades. We aimed to characterise oesophageal cancer-specific and subtypes-specific gene regulation patterns and their upstream transcription factors (TFs).  DESIGN: To identify regulatory elements, we profiled fresh-frozen oesophageal normal samples, tumours and cell lines with chromatin immunoprecipitation sequencing (ChIP-Seq). Mathematical modelling was performed to establish (super)-enhancers landscapes and interconnected transcriptional circuitry formed by master TFs. Coregulation and cooperation between master TFs were investigated by ChIP-Seq, circularised chromosome conformation capture sequencing and luciferase assay. Biological functions of candidate factors were evaluated both in vitro and in vivo.

Results: We found widespread and pervasive alterations of the (super)-enhancer reservoir in both subtypes of oesophageal cancer, leading to transcriptional activation of a myriad of novel oncogenes and signalling pathways, some of which may be exploited pharmacologically (eg, leukemia inhibitory factor (LIF) pathway). Focusing on EAC, we bioinformatically reconstructed and functionally validated an interconnected circuitry formed by four master TFs-ELF3, KLF5, GATA6 and EHF-which promoted each other's expression by interacting with each super-enhancer. Downstream, these master TFs occupied almost all EAC super-enhancers and cooperatively orchestrated EAC transcriptome. Each TF within the transcriptional circuitry was highly and specifically expressed in EAC and functionally promoted EAC cell proliferation and survival.

Conclusions: By establishing cancer-specific and subtype-specific features of the EAC epigenome, our findings promise to transform understanding of the transcriptional dysregulation and addiction of EAC, while providing molecular clues to develop novel therapeutic modalities against this malignancy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/gutjnl-2019-318325DOI Listing
April 2020

Ramucirumab plus pembrolizumab: can we make the maths work?

Lancet Oncol 2019 08 10;20(8):1041-1043. Epub 2019 Jul 10.

Department of Medicine, Division of Hematology-Oncology, University of California Los Angeles, Los Angeles, CA, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1470-2045(19)30399-7DOI Listing
August 2019

TNS1-ALK Fusion in a Recurrent, Metastatic Uterine Mesenchymal Tumor Originally Diagnosed as Leiomyosarcoma.

Acta Med Acad 2019 Apr;48(1):116-120

The Angeles Clinic and Research Institute, Los Angeles, CA, USA; Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Objective: We report a female patient diagnosed with a leiomyosarcoma and who harbored a druggable target as identified by comprehensive genomic profiling in the course of clinical care.

Case Report: The patient progressed five years after curative intent surgery and adjuvant treatment. After failure of multiple lines of chemotherapy,she was enrolled in a trial of an ALK inhibitor based on comprehensive genomic profiling (CGP) identifying an TNS1-ALK fusion.

Conclusion: In this case, identification of the ALK kinase fusion permitted enrollment in a matched mechanism driven clinical trial after exhausting standard of care treatment options. CGP raises the possibility of uterine inflammatory myofibroblastic tumor as an alternative diagnosisto leiomyosarcoma, highlighting the complementary role of CGP beyond immunohistochemical analyses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5644/ama2006-124.248DOI Listing
April 2019

Prevalence of established and emerging biomarkers of immune checkpoint inhibitor response in advanced hepatocellular carcinoma.

Oncotarget 2019 Jun 18;10(40):4018-4025. Epub 2019 Jun 18.

Foundation Medicine, Cambridge, MA, USA.

The clinical deployment of immune checkpoint inhibitors (ICIs) has created a tandem drive for the identification of biomarkers linked to benefit. Comprehensive genomic profiling was performed to evaluate the frequency of genomic biomarkers of ICI response in 755 patients with advanced hepatocellular carcinoma (HCC). Median age was 62 years' old, 73% were male, 46% had extrahepatic disease, 107 had documented hepatitis C, 96 had hepatitis B and 4 patients were coinfected. Median tumor mutation burden (TMB) was 4 mutations/Mb and only 6 tumors (0.8%) were TMB-high. Out of 542 cases assessed for microsatellite instability (MSI), one (0.2%) was MSI-high and TMB-high. Twenty-seven (4%) patients had alterations. One patient had a pathogenic R762W mutation but TMB was 4 mutations/Mb. Forty percent had DNA damage response gene alterations. In a small case series (N=17) exploring the relationship between biomarkers and ICI response, one patient (TMB 15 mutations/Mb, MSI-low) had a sustained complete response to nivolumab lasting > 2 years. Otherwise there were no significant genomic or TMB differences between responders, progressors, and those with stable disease. Overall, markers of genomic instability were infrequent in this cohort. Larger clinically annotated datasets are needed to explore genomic and non-genomic determinants of ICI response in HCC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.26998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6592287PMC
June 2019

-Altered Gastroesophageal Adenocarcinomas Are an Uncommon Clinicopathologic Entity with a Distinct Genomic Landscape.

Oncologist 2019 11 27;24(11):1462-1468. Epub 2019 Jun 27.

Department of Developmental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, California, USA.

Background: With the exception of trastuzumab, therapies directed at receptor tyrosine kinases (RTKs) in gastroesophageal adenocarcinomas (GEA) have had limited success. Recurrent fibroblast growth factor receptor 2 (FGFR2) alterations exist in GEA; however, little is known about the genomic landscape of -altered GEA. We examined alteration frequency and frequency of co-occurring alterations in GEA.

Subjects, Materials, And Methods: A total of 6,667 tissue specimens from patients with advanced GEA were assayed using hybrid capture-based genomic profiling. Tumor mutational burden (TMB) was determined on up to 1.1 Mb of sequenced DNA, and microsatellite instability was determined on 95 or 114 loci. Descriptive statistics were used to compare subgroups.

Results: We identified a total of 269 (4.0%) -altered cases consisting of -amplified (amp; 193, 72% of -altered), -mutated (36, 13%), -rearranged (re; 23, 8.6%), and cases with multiple alterations (17, 6.3%). Co-occurring alterations in other GEA RTK targets including (10%), (8%), and (3%) were observed across all classes of FGFR2-altered GEA. Co-occurring alterations in (17%), (10%), and (5.6%) were also observed frequently. Cases with FGFR2amp and FGFR2re were exclusively microsatellite stable. The median TMB for -altered GEA was 3.6 mut/mb, not significantly different from a median of 4.3 mut/mb seen in wild-type samples.

Conclusion: -altered GEA is a heterogenous subgroup with approximately 20% of -altered samples harboring concurrent RTK alterations. Putative co-occurring modifiers of FGFR2-directed therapy including oncogenic , and alterations were also frequent, suggesting that pretreatment molecular analyses may be needed to facilitate rational combination therapies and optimize patient selection for clinical trials.

Implications For Practice: Actionable receptor tyrosine kinase alterations assayed within a genomic context with therapeutic implications remain limited to amplification in gastroesophageal adenocarcinomas (GEA). Composite biomarkers and heterogeneity assessment are critical in optimizing patients selected for targeted therapies in GEA. Comprehensive genomic profiling in -altered GEA parallels the heterogeneity findings in -amplified GEA and adds support to the utility of genomic profiling in advanced gastroesophageal adenocarcinomas.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1634/theoncologist.2019-0121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6853122PMC
November 2019