Publications by authors named "Razelle Kurzrock"

637 Publications

Assessing CAR T-cell therapy response using genome-wide sequencing of cell-free DNA in patients with B-cell lymphomas.

Transplant Cell Ther 2021 Oct 13. Epub 2021 Oct 13.

WIN Consortium for Precision Medicine, Villejuif, France.

Background: Methods that enable monitoring of therapeutic efficacy of autologous chimeric antigen receptor (CAR) T-cell therapy will be clinically useful.

Objectives: The aim of this study is to demonstrate the feasibility of blood-derived cell-free DNA (cfDNA) to predict CAR T-cell therapy response in patients with refractory B-cell lymphomas.

Study Design: Whole blood was collected prior to and throughout CAR T-cell therapy until day +154. Low-coverage (∼0.4X), genome-wide cfDNA sequencing, similar to that established for non-invasive prenatal testing, was performed. The genomic instability number (GIN) was utilized to quantify plasma copy number alteration level.

Results: Twelve patients were enrolled. Seven (58%) patients achieved a complete response (CR); 2 (25%), a partial response. Median progression-free survival was 99 days; median overall survival not reached (median follow up, 247 days). Altogether, 127 blood samples were analyzed (median, 10 samples/patient (range 8-13)). All five patients who remained in CR at the time of last measurement had GIN <170 (threshold). Two patients who attained CR, but later relapsed, and all but one patient who had best response other than CR had last GIN measurement of >170. In five of six patients with relapsed or progressive disease, increasing GIN was observed prior to the diagnosis by imaging. The abundance of CAR T-cell construct (absolute number of construct copies relative to the number of human genome equivalents) also showed a trend to correlate with outcome (day 10, p=0.052).

Conclusions: These data describe a proof-of-concept for the use of multiple liquid biopsy technologies to monitor therapeutic response in B-cell lymphoma patients receiving CAR T-cell therapy.
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http://dx.doi.org/10.1016/j.jtct.2021.10.007DOI Listing
October 2021

SMARCA4: Implications of an altered chromatin-remodeling gene for cancer development and therapy.

Mol Cancer Ther 2021 Oct 12. Epub 2021 Oct 12.

Worldwide Innovative Network (WIN) for Personalized Cancer Therapy, Worldwide Innovative Network (WIN) for Personalized Cancer Therapy.

The SWI/SNF chromatin remodeling complex, via nucleosome topology modulation, regulates transcription. The SMARCA4 (BRG1) subunit codes for the ATPase energy engine of the SWI/SNF complex. SMARCA4 is a tumor suppressor that is aberrant in ~5-7% of human malignancies. Class I SMARCA4 alterations (truncating mutations, fusions, and homozygous deletion) lead to loss of function while class II alterations (missense mutations) have a dominant negative/gain-of-function effect and/or loss-of function. SMARCA4 alterations typify the ultra-rare small cell carcinomas of the ovary hypercalcemic type (SCCOHT) and SMARCA4-deficient thoracic and uterine sarcomas; they are also found in a subset of more common tumors, e.g., lung, colon, bladder, and breast carcinomas. Germline variants in the SMARCA4 gene lead to various hereditary conditions: rhabdoid tumor predisposition syndrome-2 (RTPS2), characterized by loss-of-function alterations and aggressive rhabdoid tumors presenting in infants and young children; and Coffin-Siris syndrome, characterized by dominant negative/gain-of function alterations and developmental delays, microcephaly, unique facies, and hypoplastic nails of the fifth fingers or toes. A minority of rhabdoid tumors have a germline SMARCA4 variant as do >40% of women with SCCOHT. Importantly, immune checkpoint blockade has shown remarkable, albeit anecdotal, responses in SCCOHT. Additionally, there is ongoing research into BET, EZH2, HDAC, CDK4/6, and FGFR inhibitors, as well as agents that might induce synthetic lethality via DNA damage repair impairment (ATR inhibitors and platinum chemotherapy), or via the exploitation of mitochondrial oxidative phosphorylation inhibitors or AURKA inhibitors, in SMARCA4¬-aberrant cancers.
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http://dx.doi.org/10.1158/1535-7163.MCT-21-0433DOI Listing
October 2021

Intra-patient stability of tumor mutational burden from tissue biopsies at different time points in advanced cancers.

Genome Med 2021 Oct 12;13(1):159. Epub 2021 Oct 12.

Center for Personalized Cancer Therapy, University of California San Diego (UCSD), 3855 Health Sciences Drive, La Jolla, CA, 92037, USA.

Background: Tumor mutational burden (TMB) may be a predictive biomarker of immune checkpoint inhibitor (ICI) responsiveness. Genomic landscape heterogeneity is a well-established cancer feature. Molecular characteristics may differ even within the same tumor specimen and undoubtedly evolve with time. However, the degree to which TMB differs between tumor biopsies within the same patient has not been established.

Methods: We curated data on 202 patients enrolled in the PREDICT study (NCT02478931), seen at the University of California San Diego (UCSD), who had 404 tissue biopsies for TMB (two per patient, mean of 722 days between biopsies) to assess difference in TMB before and after treatment in a pan-cancer cohort. We also performed an orthogonal analysis of 2872 paired pan-solid tumor biopsies in the Foundation Medicine database to examine difference in TMB between first and last biopsies.

Results: The mean (95% CI) TMB difference between samples was 0.583 [- 0.900-2.064] (p = 0.15). Pearson correlation showed a flat line for time elapsed between biopsies versus TMB change indicating no correlation (R = 0.0001; p = 0.8778). However, in 55 patients who received ICIs, there was an increase in TMB (before versus after mean mutations/megabase [range] 12.50 [range, 0.00-98.31] versus 14.14 [range, 0.00-100.0], p = 0.025). Analysis of 2872 paired pan-solid tumor biopsies in the Foundation Medicine database also indicated largely stable TMB patterns; TMB increases were only observed in specific tumors (e.g., breast, colorectal, glioma) within certain time intervals.

Conclusions: Overall, our results suggest that tissue TMB remains stable with time, though specific therapies such as immunotherapy may correlate with an increase in TMB.

Trial Registration: NCT02478931 , registered June 23, 2015.
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http://dx.doi.org/10.1186/s13073-021-00979-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8513181PMC
October 2021

Targeting ARID1A mutations in cancer.

Cancer Treat Rev 2021 Nov 6;100:102287. Epub 2021 Sep 6.

WIN Consortium for Personalized Cancer Therapy, USA.

Genes encoding SWI/SNF chromatin remodeling complex subunits are collectively mutated in approximately 20% of human cancers. ARID1A is a SWI/SNF subunit gene whose protein product binds DNA. ARID1A gene alterations result in loss of function. It is the most commonly mutated member of the SWI/SNF complex, being aberrant in ∼6% of cancers overall, including ovarian clear cell cancers (∼45% of patients) and uterine endometrioid cancers (∼37%). ARID1A has a crucial role in regulating gene expression that drives oncogenesis or tumor suppression. In particular, ARID1A participates in control of the PI3K/AKT/mTOR pathway, immune responsiveness to cancer, EZH2 methyltransferase activity, steroid receptor modulation, DNA damage checkpoints, and regulation of p53 targets and KRAS signaling. A variety of compounds may be of benefit in ARID1A-altered cancers: immune checkpoint blockade, and inhibitors of mTOR, EZH2, histone deacetylases, ATR and/or PARP. ARID1A alterations may also mediate resistance to platinum chemotherapy and estrogen receptor degraders/modulators.
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http://dx.doi.org/10.1016/j.ctrv.2021.102287DOI Listing
November 2021

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

Genome Med 2021 Oct 4;13(1):155. Epub 2021 Oct 4.

Center for Personalized Cancer Therapy, Moores Cancer Center, UC San Diego Health, 3855 Health Sciences Drive, Mail Code 0658, La Jolla, CA, 92093-0658, USA.

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 (R = 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.
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http://dx.doi.org/10.1186/s13073-021-00969-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8491393PMC
October 2021

Variant allele fraction of genomic alterations in circulating tumor DNA (%ctDNA) correlates with SUV in PET scan.

Am J Nucl Med Mol Imaging 2021 15;11(4):307-312. Epub 2021 Aug 15.

Center for Personalized Cancer Therapy and Division of Hematology and Oncology, Department of Medicine, University of California San Diego Moores Cancer Center La Jolla, CA, USA.

The relationship between higher variant allele fraction (VAF) of genomic alterations in circulating tumor DNA (%ctDNA), an indicator of poor outcome, and maximum standardized uptake value (SUV), the most commonly used semi-quantitative parameter in F-FDG PET/CT, has not been studied. Overall, 433 cancer patients had blood-based next generation sequencing. Maximum and sum of %ctDNA alterations (%ctDNA and %ctDNA, respectively) represent the maximum and sum of VAF, reported as a percentage. The subset of 46 eligible patients had treatment-naïve metastatic disease and PET/CT imaging, with median 13 days prior to ctDNA testing. We found a linear correlation between the maximum VAF (%ctDNA) (as well as the sum of the VAFs (%ctDNA)) and SUV of the most F-FDG-avid lesion (r=0.43, P=0.003; r=0.43, P=0.002; respectively). Our data suggest that SUV may be a non-invasive and readily available surrogate indicator for %ctDNA, a prognostic factor for patient survival. Since higher %ctDNA has been previously correlated with worse outcome, the relationship between SUV, %ctDNA and survival warrants further study.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8414395PMC
August 2021

Genome-wide Sequencing of Cell-free DNA Enables Detection of Copy-number Alterations in Patients with Cancer Where Tissue Biopsy is Not Feasible.

Mol Cancer Ther 2021 Aug 31. Epub 2021 Aug 31.

Department of Medicine, Division of Hematology/Oncology, and Center for Personalized Cancer Therapy, Moores Cancer Center, University of California, San Diego.

When tissue biopsy is not medically prudent or tissue is insufficient for molecular testing, alternative methods are needed. Because cell-free DNA (cfDNA) has been shown to provide a representative surrogate for tumor tissue, we sought to evaluate its utility in this clinical scenario. cfDNA was isolated from the plasma of patients and assayed with low-coverage (∼0.3×), genome-wide sequencing. Copy-number alterations (CNA) were identified and characterized using analytic methods originally developed for noninvasive prenatal testing (NIPT) and quantified using the genomic instability number (GIN), a metric that reflects the quantity and magnitude of CNAs across the genome. The technical variability of the GIN was first evaluated in an independent cohort comprising genome-wide sequencing results from 27,754 women who consented to have their samples used for research and whose NIPT results yielded no detected CNAs to establish a detection threshold. Subsequently, cfDNA sequencing data from 96 patients with known cancers but for whom a tissue biopsy could not be obtained are presented. An elevated GIN was detected in 35% of patients and detection rates varied by tumor origin. Collectively, CNAs covered 96.6% of all autosomes. Survival was significantly reduced in patients with an elevated GIN relative to those without. Overall, these data provide a proof of concept for the use of low-coverage, genome-wide sequencing of cfDNA from patients with cancer to obtain relevant molecular information in instances where tissue is difficult to access. These data may ultimately serve as an informative complement to other molecular tests.
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http://dx.doi.org/10.1158/1535-7163.MCT-20-1066DOI Listing
August 2021

Novel somatic alterations in unicentric and idiopathic multicentric Castleman disease.

Eur J Haematol 2021 Aug 24. Epub 2021 Aug 24.

Division of Hematology and Oncology, Department of Medicine, Center for Personalized Cancer Therapy, University of California San Diego, La Jolla, California, USA.

Objectives: Castleman disease (CD) is a heterogeneous group of disorders involving systemic inflammation and lymphoproliferation. Recently, clonal mutations have been identified in unicentric CD (UCD) and idiopathic multicentric CD (iMCD), suggesting a potential underlying neoplastic process.

Methods: Patients with UCD or iMCD with next generation sequencing (NGS) data on tissue DNA and/or circulating tumor DNA (ctDNA) were included.

Results: Five patients were included, 4 with iMCD and 1 with UCD. Four patients (80%) were women; median age was 40 years. Three of five patients (60%) had ≥1 clonal mutation detected on biopsy among the genes included in the panel. One patient with iMCD had a 14q32-1p35 rearrangement and a der(1)dup(1)(q42q21)del(1)(q42) (1q21 being IL-6R locus) on karyotype. This patient also had a NF1 K2459fs alteration on ctDNA (0.3%). Another patient with iMCD had a KDM5C Q836* mutation, and one patient with UCD had a TNS3-ALK fusion but no ALK expression by immunohistochemistry.

Conclusions: We report 4 novel somatic alterations found in patients with UCD or iMCD. The 1q21 locus contains IL-6R, and duplication of this locus may increase IL-6 expression. These findings suggest that a clonal process may be responsible for the inflammatory phenotype in some patients with UCD and iMCD.
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http://dx.doi.org/10.1111/ejh.13702DOI Listing
August 2021

Establishment of Patient-derived Succinate Dehydrogenase-deficient Gastrointestinal Stromal Tumor Models For Predicting Therapeutic Response.

Clin Cancer Res 2021 Aug 23. Epub 2021 Aug 23.

Department of Surgery, Division of Surgical Oncology, University of California, San Diego

Purpose: Gastrointestinal stromal tumor (GIST) is the most common sarcoma of the gastrointestinal tract with mutant succinate dehydrogenase () 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 or mutations, -mutant GISTs affect adolescents/young adults, often metastasize, and are frequently resistant to tyrosine kinase inhibitors (TKIs). Lack of human models for any mutant tumors, including GIST, has limited molecular characterization and drug discovery.

Experimental Design: We describe methods for establishing novel patient-derived -mutant (m) GIST models and interrogated the efficacy of temozolomide on these tumor models and in clinical trials of m GIST patients.

Results: Molecular and metabolic characterization of our patient-derived m 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 m GIST models. Translating our discovery to the clinic, a cohort of -mutant GIST patients 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.

Conclusion: We report the first methods to establish patient-derived m tumor models, which can be readily employed for understanding patient-specific tumor biology and treatment strategies. We also demonstrate that temozolomide is effective in m GIST patients who are refractory to existing chemotherapeutic drugs (namely TKIs) in clinic for GISTs, bringing a promising treatment option for these patients to clinic.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-2092DOI Listing
August 2021

Phase 1 study of M2698, a p70S6K/AKT dual inhibitor, in patients with advanced cancer.

J Hematol Oncol 2021 08 18;14(1):127. Epub 2021 Aug 18.

Moores Cancer Center, La Jolla, CA, USA.

Background: The PI3K/AKT/mTOR (PAM) pathway is a key regulator of tumor therapy resistance. We investigated M2698, an oral p70S6K/AKT dual inhibitor, in patients with advanced cancer who failed standard therapies.

Methods: M2698 was administered as monotherapy (escalation, 15-380 mg daily; food effect cohort, 240-320 mg daily) and combined with trastuzumab or tamoxifen.

Results: Overall, 101 patients were treated (M2698, n = 62; M2698/trastuzumab, n = 13; M2698/tamoxifen, n = 26). Patients were predominantly aged < 65 years, were female, had performance status 1 and were heavily pretreated. There was a dose- and concentration-dependent inhibition of pS6 levels in peripheral blood mononuclear cells and tumor tissue. M2698 was well tolerated; the most common treatment-emergent adverse events were gastrointestinal, abnormal dreams and fatigue (serious, attributed to M2698: monotherapy, 8.1%; M2698/trastuzumab, 7.7%; M2698/tamoxifen, 11.5% of patients). The recommended phase 2 doses of M2698 were 240 mg QD (monotherapy), 160 mg QD (M2698/trastuzumab) and 160 mg QD/240 mg intermittent regimen (M2698/tamoxifen). In the monotherapy cohort, 27.4% of patients had stable disease at 12 weeks; no objective response was noted. The median progression-free survival (PFS) durations in patients with PAM pathway alterations with and without confounding markers (KRAS, EGFR, AKT2) were 1.4 months and 2.8 months, respectively. Two patients with breast cancer (M2698/trastuzumab, n = 1; M2698/tamoxifen, n = 1) had partial response; their PFS durations were 31 months and 2.7 months, respectively.

Conclusions: M2698 was well tolerated. Combined with trastuzumab or tamoxifen, M2698 demonstrated antitumor activity in patients with advanced breast cancer resistant to multiple standard therapies, suggesting that it could overcome treatment resistance. Trial registration ClinicalTrials.gov, NCT01971515. Registered October 23, 2013.
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http://dx.doi.org/10.1186/s13045-021-01132-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8371902PMC
August 2021

Multicenter phase II trial (SWOG S1609, cohort 51) of ipilimumab and nivolumab in metastatic or unresectable angiosarcoma: a substudy of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART).

J Immunother Cancer 2021 Aug;9(8)

Department of Medicine, UCSD Moores Cancer Center, La Jolla, California, USA.

Purpose: Angiosarcoma is a rare aggressive endothelial cell cancer with high mortality. Isolated reports suggest immune checkpoint inhibition efficacy in angiosarcoma, but no prospective studies have been published. We report results for angiosarcoma treated with ipilimumab and nivolumab as a cohort of an ongoing rare cancer study.

Methods: This is a prospective, open-label, multicenter phase II clinical trial of ipilimumab (1 mg/kg intravenously every 6 weeks) plus nivolumab (240 mg intravenously every 2 weeks) for metastatic or unresectable angiosarcoma. Primary endpoint was objective response rate (ORR) per RECIST 1.1. Secondary endpoints include progression-free (PFS) and overall survival, and toxicity. A two-stage design was used.

Results: Overall, there were 16 evaluable patients. Median age was 68 years (range, 25-81); median number of prior lines of therapy, 2. Nine patients had cutaneous and seven non-cutaneous primary tumors. ORR was 25% (4/16). Sixty per cent of patients (3/5) with primary cutaneous scalp or face tumors attained a confirmed response. Six-month PFS was 38%. Altogether, 75% of patients experienced an adverse event (AE) (at least possibly related to drug) (25% grade 3-4 AE); 68.8%, an immune-related AE (irAE) (2 (12.5%), grade 3 or 4 irAEs (alanine aminotransferase/aspartate aminotransferase increase and diarrhea)). There were no grade 5 toxicities. One of seven patients in whom tumor mutation burden (TMB) was assessed showed a high TMB (24 mutations/mb); that patient achieved a partial response (PR). Two of three patients with PDL1 immunohistochemistry assessed had high PDL1 expression; one achieved a PR.

Conclusion: The combination of ipilimumab and nivolumab demonstrated an ORR of 25% in angiosarcoma, with three of five patients with cutaneous tumors of the scalp or face responding. Ipilimumab and nivolumab warrant further investigation in angiosarcoma.

Trial Registration Number: NCT02834013.
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http://dx.doi.org/10.1136/jitc-2021-002990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8330584PMC
August 2021

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

JCI Insight 2021 Sep 22;6(18). Epub 2021 Sep 22.

Center for Personalized Cancer Therapy, Department of Medicine, and.

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).
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http://dx.doi.org/10.1172/jci.insight.150453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8492298PMC
September 2021

Missing the target in cancer therapy.

Nat Cancer 2021 Apr 12;2:369-371. Epub 2021 Apr 12.

Center for Personalized Cancer Therapy and Division of Hematology and Oncology, Department of Medicine, University of California San Diego Moores Cancer Center, La Jolla, CA, USA.

The deployment of molecular biomarkers that are indicative of sensitivity to tumor-targeted or immune-targeted cancer therapies improves the outcome of individual patients and increases the chances of successful drug approval. However, for many lethal malignancies, the majority of clinical trials are conducted with patients who do not have biomarkers and hence they miss the target.
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http://dx.doi.org/10.1038/s43018-021-00204-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8336921PMC
April 2021

Pertuzumab and trastuzumab for HER2-positive, metastatic biliary tract cancer (MyPathway): a multicentre, open-label, phase 2a, multiple basket study.

Lancet Oncol 2021 09 30;22(9):1290-1300. Epub 2021 Jul 30.

Sarah Cannon Research Institute, Nashville, TN, USA; Tennessee Oncology, Nashville, TN, USA.

Background: Systemic therapies for metastatic biliary tract cancers are few, and patients have a median overall survival of less than 1 year. MyPathway evaluates the activity of US Food and Drug Administration-approved therapies in non-indicated tumours with potentially actionable molecular alterations. In this study, we present an analysis of patients with metastatic biliary tract cancers with HER2 amplification, overexpression, or both treated with a dual anti-HER2 regimen, pertuzumab plus trastuzumab, from MyPathway.

Methods: MyPathway is a non-randomised, multicentre, open-label, phase 2a, multiple basket study. Patients aged 18 years and older with previously treated metastatic biliary tract cancers with HER2 amplification, HER2 overexpression, or both and an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled from 23 study sites in the USA and received intravenous pertuzumab (840 mg loading dose, then 420 mg every 3 weeks) plus trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks). The primary endpoint was investigator-assessed objective response rate according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The primary outcome and adverse events were analysed in all patients who received at least one dose of pertuzumab and trastuzumab. This trial is registered with ClinicalTrials.gov, NCT02091141, and is ongoing.

Findings: 39 patients enrolled in the MyPathway HER2 biliary tract cancer cohort between Oct 28, 2014, and May 29, 2019, were evaluable for anti-tumour activity by the March 10, 2020, data cutoff date. Median follow-up was 8·1 months (IQR 2·7-15·7). Nine of 39 patients achieved a partial response (objective response rate 23% [95% CI 11-39]). Grade 3-4 treatment-emergent adverse events were reported in 18 (46%) of 39 patients, most commonly increased alanine aminotransferase and increased aspartate aminotransferase (each five [13%] of 39). Treatment-related grade 3 adverse events were reported in three (8%) of 39 patients, including increased alanine aminotransferase, aspartate aminotransferase, blood alkaline phosphatase, and blood bilirubin. Serious treatment-emergent adverse events were observed in ten (26%) of 39 patients, of which only abdominal pain occurred in more than one patient (two [5%] of 39). There were no treatment-related serious adverse events, treatment-related grade 4 events, or deaths.

Interpretation: Treatment was well tolerated in patients with previously treated HER2-positive metastatic biliary tract cancer. The response rate is promising for the initiation of randomised, controlled trials of pertuzumab plus trastuzumab in this patient population.

Funding: F Hoffmann-La Roche-Genentech.
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http://dx.doi.org/10.1016/S1470-2045(21)00336-3DOI Listing
September 2021

The Impact of COVID-19 on Cancer Clinical Trials Conducted by NCI-Designated Comprehensive Cancer Centers.

J Immunother Precis Oncol 2021 May 13;4(2):56-63. Epub 2020 Nov 13.

Center for Personalized Cancer Therapy and Division of Hematology/Oncology, University of California San Diego Moores Cancer Center, La Jolla, CA, USA.

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http://dx.doi.org/10.36401/jipo-20-30DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8320380PMC
May 2021

Signed in Blood: Circulating Tumor DNA in Cancer Diagnosis, Treatment and Screening.

Cancers (Basel) 2021 Jul 18;13(14). Epub 2021 Jul 18.

WIN Consortium, San Diego, CA 92093, USA.

With the addition of molecular testing to the oncologist's diagnostic toolbox, patients have benefitted from the successes of gene- and immune-directed therapies. These therapies are often most effective when administered to the subset of malignancies harboring the target identified by molecular testing. An important advance in the application of molecular testing is the liquid biopsy, wherein circulating tumor DNA (ctDNA) is analyzed for point mutations, copy number alterations, and amplifications by polymerase chain reaction (PCR) and/or next-generation sequencing (NGS). The advantages of evaluating ctDNA over tissue DNA include (i) ctDNA requires only a tube of blood, rather than an invasive biopsy, (ii) ctDNA can plausibly reflect DNA shedding from multiple metastatic sites while tissue DNA reflects only the piece of tissue biopsied, and (iii) dynamic changes in ctDNA during therapy can be easily followed with repeat blood draws. Tissue biopsies allow comprehensive assessment of DNA, RNA, and protein expression in the tumor and its microenvironment as well as functional assays; however, tumor tissue acquisition is costly with a risk of complications. Herein, we review the ways in which ctDNA assessment can be leveraged to understand the dynamic changes of molecular landscape in cancers.
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http://dx.doi.org/10.3390/cancers13143600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8306582PMC
July 2021

Comparative Genomic Analysis of Intrahepatic Cholangiocarcinoma: Biopsy Type, Ancestry, and Testing Patterns.

Oncologist 2021 09 18;26(9):787-796. Epub 2021 Jun 18.

Foundation Medicine Inc., Cambridge, Massachusetts, USA.

Background: At diagnosis, the majority of patients with intrahepatic cholangiocarcinoma (IHCC) present with advanced disease and a poor prognosis. Comprehensive genomic profiling (CGP) early in the disease course may increase access to targeted therapies and clinical trials; however, unresolved issues remain surrounding the optimal biopsy type to submit for CGP.

Patients And Methods: Mutational frequencies between primary tumor biopsies (Pbx), metastatic biopsies (Mbx), and liquid biopsies (Lbx) in 1,632 patients with IHCC were compared.

Results: Potentially actionable alterations were found in 52%, 34%, and 35% of patients in the Pbx, Mbx, and Lbx cohorts, respectively. In Pbx, Mbx, and Lbx, FGFR2 rearrangements were found in 9%, 6%, and 4%, and IDH1 mutations were identified in 16%, 5%, and 9% patients, respectively. Moreover, alterations in FGFR2 and IDH1 were significantly associated with distinct ancestries, including 2.1-fold enrichment for FGFR2 rearrangements in patients with African ancestry and 1.5-fold enrichment for IDH1 mutations in patients with admixed American (Hispanic) ancestry. Finally, the publication of biomarker-driven clinical trials in IHCC correlated with changing CGP testing patterns. Significant correlations between patient characteristics and IHCC trial disclosures were observed, including a significant decrease from time between biopsy and CGP testing, and more frequent testing of primary versus metastatic samples.

Conclusion: Overall, because of the high likelihood of identifying actionable genomic alterations, CGP should be considered for the majority of patients with inoperable IHCC, and Lbx and Mbx can be considered as part of the diagnostic suite.

Implications For Practice: Comprehensive genomic profiling (CGP) should be considered for all patients with intrahepatic cholangiocarcinoma (IHCC) or suspected IHCC, as actionable alterations were commonly found in multiple genes and a wide variety of FGFR2 fusion partners were identified. The disclosure of IHCC trial data correlated with increased use of CGP, an encouraging trend that moves new therapeutic options forward for rare cancers with a rare biomarker. Although tissue from the primary lesion may identify actionable alterations at higher rates, CGP of a liquid biopsy or metastatic site can be considered, particularly if the primary tissue block is exhausted.
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http://dx.doi.org/10.1002/onco.13844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8417854PMC
September 2021

Moving Beyond 3+3: The Future of Clinical Trial Design.

Am Soc Clin Oncol Educ Book 2021 Jun;41:e133-e144

Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX.

Misgivings have been raised about the operating characteristics of the canonical 3+3 dose-escalation phase I clinical trial design. Yet, the traditional 3+3 design is still the most commonly used. Although it has been implied that adhering to this design is due to a stubborn reluctance to adopt change despite other designs performing better in hypothetical computer-generated simulation models, the continued adherence to 3+3 dose-escalation phase I strategies is more likely because these designs perform the best in the real world, pinpointing the correct dose and important side effects with an acceptable degree of precision. Beyond statistical simulations, there are little data to refute the supposed shortcomings ascribed to the 3+3 method. Even so, to address the unique nuances of gene- and immune-targeted compounds, a variety of inventive phase 1 trial designs have been suggested. Strategies for developing these therapies have launched first-in-human studies devised to acquire a breadth of patient data that far exceed the size of a typical phase I design and blur the distinction between dose selection and efficacy evaluation. Recent phase I trials of promising cancer therapies assessed objective tumor response and durability at various doses and schedules as well as incorporated multiple expansion cohorts spanning a variety of histology or biomarker-defined tumor subtypes, sometimes resulting in U.S. Food and Drug Administration approval after phase I. This article reviews recent innovations in phase I design from the perspective of multiple stakeholders and provides recommendations for future trials.
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http://dx.doi.org/10.1200/EDBK_319783DOI Listing
June 2021

Digital Display Precision Predictor: the prototype of a global biomarker model to guide treatments with targeted therapy and predict progression-free survival.

NPJ Precis Oncol 2021 Apr 28;5(1):33. Epub 2021 Apr 28.

American Society of Clinical Oncology (ASCO), Alexandria, VA, USA.

The expanding targeted therapy landscape requires combinatorial biomarkers for patient stratification and treatment selection. This requires simultaneous exploration of multiple genes of relevant networks to account for the complexity of mechanisms that govern drug sensitivity and predict clinical outcomes. We present the algorithm, Digital Display Precision Predictor (DDPP), aiming to identify transcriptomic predictors of treatment outcome. For example, 17 and 13 key genes were derived from the literature by their association with MTOR and angiogenesis pathways, respectively, and their expression in tumor versus normal tissues was associated with the progression-free survival (PFS) of patients treated with everolimus or axitinib (respectively) using DDPP. A specific eight-gene set best correlated with PFS in six patients treated with everolimus: AKT2, TSC1, FKB-12, TSC2, RPTOR, RHEB, PIK3CA, and PIK3CB (r = 0.99, p = 5.67E-05). A two-gene set best correlated with PFS in five patients treated with axitinib: KIT and KITLG (r = 0.99, p = 4.68E-04). Leave-one-out experiments demonstrated significant concordance between observed and DDPP-predicted PFS (r = 0.9, p = 0.015) for patients treated with everolimus. Notwithstanding the small cohort and pending further prospective validation, the prototype of DDPP offers the potential to transform patients' treatment selection with a tumor- and treatment-agnostic predictor of outcomes (duration of PFS).
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http://dx.doi.org/10.1038/s41698-021-00171-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080819PMC
April 2021

A phase II basket trial of Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors (DART) SWOG S1609: High-grade neuroendocrine neoplasm cohort.

Cancer 2021 Sep 21;127(17):3194-3201. Epub 2021 Apr 21.

Moores Cancer Center, University of California at San Diego, La Jolla, California.

Background: The authors previously reported the results of the nonpancreatic neuroendocrine neoplasm cohort of the SWOG S1609 DART (Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors) trial, which permitted all histologic grades and had a 44% overall response rate (ORR) among patients with high-grade disease. Here they sought to validate their findings in a dedicated prospective cohort of high-grade neuroendocrine neoplasms within S1609.

Methods: A prospective, open-label, multicenter, phase 2 clinical trial of ipilimumab plus nivolumab was conducted across multiple rare tumor cohorts. The dedicated, high-grade neuroendocrine neoplasm cohort was examined here. The primary end point was the ORR according to version 1.1 of the Response Evaluation Criteria in Solid Tumors. Secondary end points included progression-free survival (PFS), overall survival (OS), and toxicity.

Results: Nineteen patients with high-grade neuroendocrine neoplasms (defined by local pathology review) were enrolled in this cohort of S1609. The most common primary sites were unknown primaries (21%), which were followed by the rectum, gastroesophageal junction, cervix, and pancreas (11%). The median number of lines of prior therapy was 1 (range, 0-3). All patients were microsatellite-stable. The median Ki-67 value was 80%. The ORR was 26% (95% confidence interval [CI], 11%-45%), and the clinical benefit rate (stable disease for ≥6 months plus partial responses plus complete responses) was 32% (95% CI, 13%-57%). The 6-month PFS rate was 32% (95% CI, 16%-61%) with a median PFS of 2.0 months (95% CI, 1.8 months to ∞) and a median OS of 8.7 months (95% CI, 6.1 months to ∞). The most common toxicities were fatigue (32%) and rash (26%), and the most common grade 3/4 immune-related adverse event was rash (15%); there were no events that required treatment discontinuation and no grade 5 events.

Conclusions: Ipilimumab plus nivolumab demonstrated a 26% ORR in patients with high-grade neuroendocrine neoplasms, with durable responses seen in patients with refractory disease.
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http://dx.doi.org/10.1002/cncr.33591DOI Listing
September 2021

Functional measurement of mitogen-activated protein kinase pathway activation predicts responsiveness of RAS-mutant cancers to MEK inhibitors.

Eur J Cancer 2021 05 14;149:184-192. Epub 2021 Apr 14.

Center for Personalized Cancer Therapy, University of California San Diego Moores Cancer Center, La Jolla, CA, USA. Electronic address:

Background: RAS variant-related functional impact on the mitogen-activated protein kinase (MAPK) pathway, and correlation between MAPK activation and MAPK/ERK kinase (MEK) inhibitor responsiveness, is not established.

Patients And Methods: Of 1,693 tumours sequenced, 576 harboured a RAS alteration; 62 patients received an MEK inhibitor (MEKi) and had RAS mutations that were functionally characterised. We report that RAS mutants have variable levels of MAPK activity, as measured by a functional cell-based assay that quantified MAPK pathway activation after transfection with a variety of RAS mutations.

Results: Patients with tumours harbouring RAS alterations with high versus low MAPK activity who were treated with an MEKi showed significantly longer median progression-free survival (PFS) (5.0 vs. 2.3 months; p = 0.0034) and overall survival (20.0 vs. 5.0 months; p = 0.0146) and a trend towards higher rates of clinical benefit (stable disease ≥6 months or partial/complete remission) (38% versus 15%; p = 0.095) (p-values as per univariate analysis). PFS remained statistically significant after the multivariate analysis (p = 0.003).

Conclusions: These results support a correlation between RAS-mutant cancers with greater MAPK signalling and PFS after MEKi treatment.
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http://dx.doi.org/10.1016/j.ejca.2021.01.055DOI Listing
May 2021

Tumor Lysis Syndrome: Introduction of a Cutaneous Variant and a New Classification System.

Cureus 2021 Mar 11;13(3):e13816. Epub 2021 Mar 11.

Center for Personalized Cancer Therapy, University of California San Diego Moores Cancer Center, La Jolla, USA.

Tumor lysis syndrome, an oncological emergency, is characterized by laboratory parameters such as hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia, as well as renal injury with an elevated creatinine. Tumor lysis syndrome is seen in patients with aggressive malignancies and high tumor burden. More frequently, it occurs in individuals with hematologic malignancies such as high-grade lymphomas (such as Burkitt lymphoma) and leukemia (such as acute lymphocytic leukemia). It also, albeit less commonly, can be seen in patients with widespread solid tumors that are rapidly proliferating and are markedly sensitivity to antineoplastic therapy. Tumor lysis syndrome is usually preceded by cancer-directed therapy; however, the syndrome can present spontaneously prior to the individual receiving malignancy-directed treatment. We reported a man with metastatic salivary duct carcinoma who had cutaneous metastases that presented as carcinoma hemorrhagiectoides. Microscopic examination demonstrated that the metastatic tumor cells had infiltrated and replaced the entire dermis. After the patient received his first dose of antineoplastic therapy, he had an excellent response and the cutaneous metastases developed into ulcers; we hypothesize that most of the dermis, which had been replaced by tumor cells, disappeared as a result of the therapeutic response, and the overlying epidermis became necrotic and shed, leaving an ulcer. His dramatic response to treatment prompted us to propose a new classification of tumor lysis syndrome, which should include the systemic form of the condition as well as the new variant: cutaneous tumor lysis syndrome. We anticipate that, with improvement in targeted therapies, there may be an increase in therapy-associated cutaneous tumor lysis syndrome.
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http://dx.doi.org/10.7759/cureus.13816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038896PMC
March 2021

Synthetic lethality-mediated precision oncology via the tumor transcriptome.

Cell 2021 04 14;184(9):2487-2502.e13. Epub 2021 Apr 14.

Cancer Data Science Lab, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address:

Precision oncology has made significant advances, mainly by targeting actionable mutations in cancer driver genes. Aiming to expand treatment opportunities, recent studies have begun to explore the utility of tumor transcriptome to guide patient treatment. Here, we introduce SELECT (synthetic lethality and rescue-mediated precision oncology via the transcriptome), a precision oncology framework harnessing genetic interactions to predict patient response to cancer therapy from the tumor transcriptome. SELECT is tested on a broad collection of 35 published targeted and immunotherapy clinical trials from 10 different cancer types. It is predictive of patients' response in 80% of these clinical trials and in the recent multi-arm WINTHER trial. The predictive signatures and the code are made publicly available for academic use, laying a basis for future prospective clinical studies.
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http://dx.doi.org/10.1016/j.cell.2021.03.030DOI Listing
April 2021

Maternal to fetal transmission of cancer: implications for molecular tumor testing, immune regulation, and pediatric malignancies.

Med (N Y) 2021 Mar;2(3):211-213

Center for Personalized Cancer Therapy and Division of Hematology and Oncology, Department of Medicine, University of California San Diego Moores Cancer Center, La Jolla, CA 92093, USA.

Molecular tumor testing has transformed the treatment of patients with malignancies and is helping catalyze the development of novel therapeutic strategies. In a recent issue of , Arakawa et al. describe two cases of pediatric lung cancer resulting from mother-to-infant transmission, diagnosed remote from delivery..
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http://dx.doi.org/10.1016/j.medj.2021.02.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040028PMC
March 2021

Wedding of Molecular Alterations and Immune Checkpoint Blockade: Genomics as a Matchmaker.

J Natl Cancer Inst 2021 Apr 6. Epub 2021 Apr 6.

The University of Texas MD Anderson Cancer Center, Department of Investigational Cancer Therapeutics, Houston, TX, USA.

The development of checkpoint blockade immunotherapy has transformed the medical oncology armamentarium. But, despite its favorable impact on clinical outcomes, immunotherapy benefits only a subset of patients, and a substantial proportion of these individuals eventually manifest resistance. Serious immune-related adverse events and hyper-progression have also been reported. It is therefore essential to understand the molecular mechanisms and identify the drivers of therapeutic response and resistance. In this review, we provide an overview of the current and emerging clinically relevant genomic biomarkers implicated in checkpoint blockade outcome. U.S. Food and Drug Administration-approved molecular biomarkers of immunotherapy response include mismatch repair deficiency/microsatellite instability and tumor mutational burden ≥10 mutations/megabase. Investigational genomic-associated biomarkers for immunotherapy response include alterations of the following genes/associated pathways: chromatin remodeling (ARID1A, PBRM1, SMARCA4, SMARCB1, BAP1), major histocompatibility complex, specific (e.g., ultraviolet, APOBEC) mutational signatures, T-cell receptor repertoire, PDL1, POLE/POLD1, and neo-antigens produced by the mutanome; those potentially associated with resistance include β2-microglobulin, EGFR, Keap1, JAK1/JAK2/interferon-gamma signaling, MDM2, PTEN, STK11, and Wnt/Beta-catenin pathway alterations. Prospective clinical trials are needed to assess the role of a composite of these biomarkers in order to optimize the implementation of precision immunotherapy in patient care.
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http://dx.doi.org/10.1093/jnci/djab067DOI Listing
April 2021

STK11 alterations in the pan-cancer setting: prognostic and therapeutic implications.

Eur J Cancer 2021 05 19;148:215-229. Epub 2021 Mar 19.

Center for Personalized Cancer Therapy, University of California, Moores Cancer Center, La Jolla, CA, 92093, USA.

Background: STK11 is an important tumour suppressor gene reported to confer immunotherapy resistance in non-small-cell lung cancers (NSCLC) especially in the presence of KRAS co-alterations.

Methods: This study analysed 4446 patients for whom next-generation sequencing of tissue and/or circulating tumour DNA (ctDNA) had been performed.

Results: Overall, 60 of 4446 tumours (1.35%) harboured STK11 alterations. STK11 alterations were associated with shorter median time to progression and overall survival (OS) across cancers from diagnosis: 6.4 months (5.1-7.9) versus 12 months (11.7-12.3; p = 0.001); and 20.5 (17.4-23.5) versus 29.1 (26.9-31.3; p = 0.03), respectively (pan-cancer). Pan-cancers, the median progression-free survival (PFS; 95% CI) for first-line therapy (regardless of treatment type) for those with co-altered STK11 and KRAS (N = 27; versus STK11-altered and KRAS wild type [N = 33]), was significantly shorter (3 [1.3-4.7] versus 10 [4.9-15.7] months, p < 0.0005, p multivariate, 0.06); the median OS also was also shorter (p multivariate = 0.02). In pan-cancer patients treated with checkpoint blockade, STK11 and KRAS co-altered versus STK11-altered/KRAS wild type had a shorter median PFS and trend toward shorter OS (p = 0.04 and p = 0.06, respectively). In contrast, in examining STK11-altered versus wild-type pan-cancer patients treated with checkpoint blockade immunotherapy, the two groups showed no difference in outcome (PFS [p = 0.4]; OS [p = 0.7]); STK11-altered versus wild-type lung cancer patients also did not fare worse on immunotherapy.

Conclusions: Across cancers, STK11 alterations correlated with a poor prognosis regardless of therapy. However, STK11 alterations alone did not associate with inferior immunotherapy outcome in the pan-cancer setting or in NSCLC. Pan-cancer patients with co-altered STK11/KRAS did worse, regardless of treatment type.
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http://dx.doi.org/10.1016/j.ejca.2021.01.050DOI Listing
May 2021

V600E/V600K Mutations versus Nonstandard Alterations: Prognostic Implications and Therapeutic Outcomes.

Mol Cancer Ther 2021 06 15;20(6):1072-1079. Epub 2021 Mar 15.

Center for Personalized Cancer Therapy and Division of Hematology and Oncology, UC San Diego Moores Cancer Center, San Diego, California.

BRAF and MEK inhibitors are standard of care for V600E/K-mutated melanoma, but the benefit of BRAF and/or MEK inhibitors for nonstandard alterations for melanoma and other cancers is unclear. Patients with diverse malignancies whose cancers had undergone next-generation sequencing were screened for alterations. Demographics, treatment with BRAF and/or MEK inhibitors, clinical response, progression-free survival (PFS), and overall survival (OS) were determined from review of the electronic medical records for patients with standard V600E/K versus nonstandard alterations. A total of 213 patients with alterations (87 with nonstandard alterations) were identified; OS from diagnosis was significantly worse with nonstandard versus standard alterations, regardless of therapy [HR (95% confidence interval), 0.58 (0.38-0.88); = 0.01]. Overall, 45 patients received BRAF/MEK-directed therapy (eight with nonstandard alterations); there were no significant differences in clinical benefit rate [stable disease ≥6 months/partial/complete response (74% vs. 63%; = 0.39) or PFS ( = 0.24; vs. others)]. In conclusion, patients with nonstandard versus standard alterations ( V600E/K) have a worse prognosis with shorter survival from diagnosis. Even so, 63% of patients with nonstandard alterations achieved clinical benefit with BRAF/MEK inhibitors. Larger prospective studies are warranted to better understand the prognostic versus predictive implication of standard versus nonstandard alterations.
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http://dx.doi.org/10.1158/1535-7163.MCT-20-0861DOI Listing
June 2021

A Phase 1b Study to Evaluate the Safety and Efficacy of Durvalumab in Combination With Tremelimumab or Danvatirsen in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma.

Clin Lymphoma Myeloma Leuk 2021 05 17;21(5):309-317.e3. Epub 2020 Dec 17.

Division of Hematology & Oncology, MUSC Health Hollings Cancer Center, Charleston, SC.

Background: Despite recent advances, outcomes in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) remain poor. Immune checkpoint inhibitors have shown limited efficacy in this setting, but combinations with novel agents may enhance benefit. Combination therapy with durvalumab, an anti-programmed death ligand 1 (PD-L1) antibody, and danvatirsen (AZD9150; an antisense oligonucleotide inhibiting signal transducer and activator of transcription 3 [STAT3]) or tremelimumab (an anti-cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4] antibody) may augment endogenous antitumor activity.

Patients And Methods: In this phase 1b dose escalation and dose expansion study, we evaluated durvalumab 20 mg/kg every 4 weeks plus either tremelimumab 1 mg/kg every 4 weeks or danvatirsen 2 or 3 mg/kg (administered on days 1, 3, 5, 8, 15, and 22, then every week). Treatment continued until disease progression. The primary endpoint was safety; secondary endpoints included efficacy, pharmacokinetics, and immunogenicity.

Results: As of April 4, 2019, 32 patients were enrolled and treated, receiving a median of 2 prior lines of systemic therapy. Treatment-related adverse events occurred in 21 patients (65.6%), most commonly alanine aminotransferase/aspartate aminotransferase increased (grade 1-3), anemia (grade 1-3), and fatigue (grade 1). The overall objective response rate was 6.3%, with 2 partial responses. Median time to response was 11.0 weeks (range, 7.7-14.3 weeks). Median progression-free survival was 7.4 weeks (range, 0.1-31.4 weeks), and median overall survival was 28.0 weeks (range, 1.9-115.4 weeks).

Conclusion: The primary endpoint was met, with durvalumab plus tremelimumab/danvatirsen generally well tolerated in patients with relapsed/refractory DLBCL; however, antitumor activity was limited.
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http://dx.doi.org/10.1016/j.clml.2020.12.012DOI Listing
May 2021

Cutaneous Metastatic Cancer: Carcinoma Hemorrhagiectoides Presenting as the Shield Sign.

Cureus 2021 Jan 11;13(1):e12627. Epub 2021 Jan 11.

Center for Personalized Cancer Therapy, University of California San Diego Moores Cancer Center, La Jolla, USA.

Cutaneous metastases can be either the initial presentation of an unsuspected internal neoplasm in a cancer-free individual, or the harbinger of recurrent malignancy in an oncology patient who had achieved remission of his cancer, or a sign of progressive disease in a cancer patient who is currently receiving antineoplastic treatment. The cutaneous presentation of skin metastases is pleomorphic and can mimic not only benign conditions and tumors of the skin but also infections and inflammation of the skin. Carcinoma erysipelatoides, carcinoma hemorrhagiectoides, and carcinoma telangiectoides are the three subtypes of inflammatory cutaneous metastatic cancer. The former masquerades as a cutaneous streptococcal infection whereas the latter mimics idiopathic telangiectasias. In contrast, the morphology of carcinoma hemorrhagiectoides is distinctive: it appears similar in shape to a medieval knight's shield and its presence is referred to as a positive shield sign. To the best of our knowledge, carcinoma hemorrhagiectoides has been reported in four oncology patients whose skin metastases presented with the shield sign: two men with salivary duct carcinoma and two women with breast cancer. In conclusion, the shield sign may not only be a pathognomonic clinical feature of carcinoma hemorrhagiectoides but also reflect a common genomic aberration of these metastatic tumors.
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http://dx.doi.org/10.7759/cureus.12627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872488PMC
January 2021

Immune profiling and immunotherapeutic targets in pancreatic cancer.

Ann Transl Med 2021 Jan;9(2):119

OmniSeq, Inc., Buffalo, NY, USA.

Background: Immunotherapeutic approaches for pancreatic ductal adenocarcinoma (PDAC) are less successful as compared to many other tumor types. In this study, comprehensive immune profiling was performed in order to identify novel, potentially actionable targets for immunotherapy.

Methods: Formalin-fixed paraffin embedded (FFPE) specimens from 68 patients were evaluated for expression of 395 immune-related markers (RNA-seq), mutational burden by complete exon sequencing of 409 genes, PD-L1 expression by immunohistochemistry (IHC), pattern of tumor infiltrating lymphocytes (TILs) infiltration by CD8 IHC, and PD-L1/L2 copy number by fluorescent in situ hybridization (FISH).

Results: The seven classes of actionable genes capturing myeloid immunosuppression, metabolic immunosuppression, alternative checkpoint blockade, CTLA-4 immune checkpoint, immune infiltrate, and programmed cell death 1 (PD-1) axis immune checkpoint, discerned 5 unique clinically relevant immunosuppression expression profiles (from most to least common): (I) combined myeloid and metabolic immunosuppression [affecting 25 of 68 patients (36.8%)], (II) multiple immunosuppressive mechanisms (29.4%), (III) PD-L1 positive (20.6%), (IV) highly inflamed PD-L1 negative (10.3%); and (V) immune desert (2.9%). The Wilcoxon rank-sum test was used to compare the PDAC cohort with a comparison cohort (n=1,416 patients) for the mean expressions of the 409 genes evaluated. Multiple genes including TIM3, VISTA, CCL2, CCR2, TGFB1, CD73, and CD39 had significantly higher mean expression versus the comparison cohort, while three genes (LAG3, GITR, CD38) had significantly lower mean expression.

Conclusions: This study demonstrates that a clinically relevant unique profile of immune markers can be identified in PDAC and be used as a roadmap for personalized immunotherapeutic decision-making strategies.
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http://dx.doi.org/10.21037/atm-20-1076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867882PMC
January 2021
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