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1.  Consensus Recommendations to Accelerate Clinical Trials for Neurofibromatosis Type 2 
Purpose
Neurofibromatosis type 2 (NF2) is a rare autosomal dominant disorder associated primarily with bilateral schwannomas seen on the superior vestibular branches of the eighth cranial nerves. Significant morbidity can result from surgical treatment of these tumors. Meningiomas, ependymomas, and other benign central nervous system tumors are also common in NF2. The lack of effective treatments for NF2 marks an unmet medical need.
Experimental Design
Here, we provide recommendations from a workshop, cochaired by Drs. D. Gareth Evans and Marco Giovannini, of 36 international researchers, physicians, representatives of the biotechnology industry, and patient advocates on how to accelerate progress toward NF2 clinical trials.
Results
Workshop participants reached a consensus that, based on current knowledge, the time is right to plan and implement NF2 clinical trials. Obstacles impeding NF2 clinical trials and how to address them were discussed, as well as the candidate therapeutic pipeline for NF2.
Conclusions
Both phase 0 and phase II NF2 trials are near-term options for NF2 clinical trials. The number of NF2 patients in the population remains limited, and successful recruitment will require ongoing collaboration efforts between NF2 clinics.
doi:10.1158/1078-0432.CCR-08-3011
PMCID: PMC4513640  PMID: 19671848
2.  A Phase I First-in-Human Trial of Bardoxolone Methyl in Patients with Advanced Solid Tumors and Lymphomas 
Purpose
Bardoxolone methyl, a novel synthetic triterpenoid and antioxidant inflammation modulator, potently induces Nrf2 and inhibits NF-κB and Janus-activated kinase/STAT signaling. This first-in-human phase I clinical trial aimed to determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), and appropriate dose for phase II studies; characterize pharmacokinetic and pharmacodynamic parameters; and assess antitumor activity.
Experimental Design
Bardoxolone methyl was administered orally once daily for 21 days of a 28-day cycle. An accelerated titration design was employed until a grade 2–related adverse event occurred. A standard 3 + 3 dose escalation was then employed until the MTD was reached. Single dose and steady-state plasma pharmacokinetics of the drug were characterized. Assessment of Nrf2 activation was examined in peripheral blood mononuclear cells (PBMC) by measuring NAD(P)H:quinone oxidoreductase (NQO1) mRNA levels. Immunohistochemical assessment of markers of inflammation, cell cycle, and apoptosis was carried out on tumor biopsies.
Results
The DLTs were grade 3 reversible liver transaminase elevations. The MTD was established as 900 mg/d. A complete tumor response occurred in a mantle cell lymphoma patient, and a partial response was observed in an anaplastic thyroid carcinoma patient. NQO1 mRNA levels increased in PBMCs, and NF-κB and cyclin D1 levels decreased in tumor biopsies. Estimated glomerular filtration rate (eGFR) was also increased.
Conclusions
Bardoxolone methyl was well tolerated with an MTD of 900 mg/d. The increase in eGFR suggests that bardoxolone methyl might be beneficial in chronic kidney disease. Objective tumor responses and pharmacodynamic effects were observed, supporting continued development of other synthetic triterpenoids in cancer.
doi:10.1158/1078-0432.CCR-11-2703
PMCID: PMC4494099  PMID: 22634319
3.  A PHASE 1 STUDY OF GEMCITABINE COMBINED WITH DASATINIB IN PATIENTS WITH ADVANCED SOLID TUMORS 
Investigational new drugs  2012;31(4):918-926.
Purpose
Dasatinib has been shown preclinically to overcome resistance to gemcitabine. We evaluated the safety and biological activity of the combination of dasatinib and gemcitabine in patients with advanced solid tumors.
Experimental Design
In a phase 1 study (3+3 design), patients received daily dasatinib with weekly gemcitabine on days 1, 8 and 15 of a 28-day cycle (except cycle 1 which was eight weeks). Dose escalation began with dasatinib 70mg orally (PO) daily and gemcitabine 800mg/m2 intravenously (IV) weekly.
Results
Forty-seven patients (15 men; median age = 55 years; median number of prior systemic treatments = 4) were enrolled. Dose-limiting toxicities were grade 3 fatigue and dehydration, with the maximum tolerated dose being dasatinib 100mg PO qd and gemcitabine 600mg/m2 IV weekly. The most common grade 3–4 toxicities were anemia (21.5%), thrombocytopenia (26.2%), leukopenia (26.2%), and pleural effusion (10.7%). Six of 47 patients attained stable disease (SD) ≥ 6 months or partial response including 2 of 8 patients with pancreatic cancer (SD ≥ 6 months; both gemcitabine-refractory), 2 of 3 patients with thymoma (SD for 9.8 and 15 months), 1 of 1 patient with anal squamous cancer (SD 15 months) and 1 of 5 patients with inflammatory breast cancer. No significant changes in circulating tumor cells or interleukin-8 levels were observed.
Conclusions
The combination was well tolerated at doses of dasatinib 100mg PO daily and gemcitabine 600mg/m2 IV weekly. SD ≥ 6 months/ PR was observed in gemcitabine-refractory pancreatic cancer, thymoma, anal cancer and inflammatory breast cancer.
doi:10.1007/s10637-012-9898-3
PMCID: PMC4482128  PMID: 23179336
dasatinib; gemcitabine; pancreatic cancer; phase 1; advanced solid tumors
4.  Personalized Medicine in a Phase I Clinical Trials Program: The MD Anderson Cancer Center Initiative 
Purpose
We initiated a personalized medicine program in the context of early clinical trials, using targeted agents matched with tumor molecular aberrations. Herein, we report our observations.
Patient and Methods
Patients with advanced cancer were treated in the Clinical Center for Targeted Therapy. Molecular analysis was conducted in the MD Anderson Clinical Laboratory Improvement Amendments (CLIA) -certified laboratory. Patients whose tumors had an aberration were treated with matched targeted therapy, when available. Treatment assignment was not randomized. The clinical outcomes of patients with molecular aberrations treated with matched targeted therapy were compared with those of consecutive patients who were not treated with matched targeted therapy.
Results
Of 1,144 patients analyzed, 460 (40.2%) had 1 or more aberration. In patients with 1 molecular aberration, matched therapy (n = 175) compared with treatment without matching (n = 116) was associated with a higher overall response rate (27% vs. 5%; P < 0.0001), longer time-to-treatment failure (TTF; median, 5.2 vs. 2.2 months; P< 0.0001), and longer survival (median, 13.4 vs. 9.0 months; P= 0.017). Matched targeted therapy was associated with longer TTF compared with their prior systemic therapy in patients with 1 mutation (5.2 vs. 3.1 months, respectively; P < 0.0001). In multivariate analysis in patients with 1 molecular aberration, matched therapy was an independent factor predicting response (P = 0.001) and TTF (P = 0.0001).
Conclusion
Keeping in mind that the study was not randomized and patients had diverse tumor types and a median of 5 prior therapies, our results suggest that identifying specific molecular abnormalities and choosing therapy based on these abnormalities is relevant in phase I clinical trials.
doi:10.1158/1078-0432.CCR-12-1627
PMCID: PMC4454458  PMID: 22966018
5.  Molecular Tumor Board: The University of California San Diego Moores Cancer Center Experience 
The Oncologist  2014;19(6):631-636.
Genomic sequencing is revealing complex molecular profiles that differ by patient. A molecular tumor board was initiated to provide expert multidisciplinary input for patients with tumors. Results showed that multidisciplinary molecular tumor boards may help optimize management. Barriers to personalized therapy include access to appropriately targeted drugs.
Objective.
DNA sequencing tests are enabling physicians to interrogate the molecular profiles of patients’ tumors, but most oncologists have not been trained in advanced genomics. We initiated a molecular tumor board to provide expert multidisciplinary input for these patients.
Materials and Methods.
A team that included clinicians, basic scientists, geneticists, and bioinformatics/pathway scientists with expertise in various cancer types attended. Molecular tests were performed in a Clinical Laboratory Improvement Amendments environment.
Results.
Patients (n = 34, since December 2012) had received a median of three prior therapies. The median time from physician order to receipt of molecular diagnostic test results was 27 days (range: 14–77 days). Patients had a median of 4 molecular abnormalities (range: 1–14 abnormalities) found by next-generation sequencing (182- or 236-gene panels). Seventy-four genes were involved, with 123 distinct abnormalities. Importantly, no two patients had the same aberrations, and 107 distinct abnormalities were seen only once. Among the 11 evaluable patients whose treatment had been informed by molecular diagnostics, 3 achieved partial responses (progression-free survival of 3.4 months, ≥6.5 months, and 7.6 months). The most common reasons for being unable to act on the molecular diagnostic results were that patients were ineligible for or could not travel to an appropriately targeted clinical trial and/or that insurance would not cover the cognate agents.
Conclusion.
Genomic sequencing is revealing complex molecular profiles that differ by patient. Multidisciplinary molecular tumor boards may help optimize management. Barriers to personalized therapy include access to appropriately targeted drugs.
doi:10.1634/theoncologist.2013-0405
PMCID: PMC4041669  PMID: 24797821
Cancer; Molecular tumor board; Molecular profile; Personalized; Mutation
6.  Multiple gene aberrations and breast cancer: lessons from super-responders 
BMC Cancer  2015;15:442.
Background
The presence of multiple molecular aberrations in patients with breast cancer may correlate with worse outcomes.
Case Presentations
We performed in-depth molecular analysis of patients with estrogen receptor-positive, HER2-negative, hormone therapy-refractory breast cancer, who achieved partial or complete responses when treated with anastrozole and everolimus. Tumors were analyzed using a targeted next generation sequencing (NGS) assay in a Clinical Laboratory Improvement Amendments laboratory. Genomic libraries were captured for 3,230 exons in 182 cancer-related genes plus 37 introns from 14 genes often rearranged in cancer and sequenced to high coverage. Patients received anastrozole (1 mg PO daily) and everolimus (5 or 10 mg PO daily). Thirty-two patients with breast cancer were treated on study and 5 (16 %) achieved a partial or complete response. Primary breast tissue was available for NGS testing in three of the responders (partial response with progression free survival of 11 and 14 months, respectively; complete response with progression free survival of 9+ months). The following molecular aberrations were observed: PTEN loss by immunohistochemistry, CCDN1 and FGFR1 amplifications, and PRKDC re-arrangement (NGS) (patient #1); PIK3CA and PIK3R1 mutations, and CCDN1, FGFR1, MYC amplifications (patient #2); TP53 mutation, CCNE1, IRS2 and MCL1 amplifications (patient #3). Some (but not all) of these aberrations converge on the PI3K/AKT/mTOR pathway, perhaps accounting for response.
Conclusions
Patients with estrogen receptor-positive breast cancer can achieve significant responses on a combination of anastrozole and everolimus, even in the presence of multiple molecular aberrations. Further study of next generation sequencing-profiled tumors for convergence and resistance pathways is warranted.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-015-1439-y) contains supplementary material, which is available to authorized users.
doi:10.1186/s12885-015-1439-y
PMCID: PMC4446801  PMID: 26021831
Breast cancer; Genomic aberrations; Next generation sequencing
7.  Actionable mutations in plasma cell-free DNA in patients with advanced cancers referred for experimental targeted therapies 
Oncotarget  2015;6(14):12809-12821.
Cell-free (cf) DNA in the plasma of cancer patients offers an easily obtainable source of biologic material for mutation analysis. Plasma samples from 157 patients with advanced cancers who progressed on systemic therapy were tested for 21 mutations in BRAF, EGFR, KRAS, and PIK3CA using the BEAMing method and results were compared to mutation analysis of archival tumor tissue from a CLIA-certified laboratory obtained as standard of care from diagnostic or therapeutic procedures. Results were concordant for archival tissue and plasma cfDNA in 91% cases for BRAF mutations (kappa = 0.75, 95% confidence interval [CI] 0.63 – 0.88), in 99% cases for EGFR mutations (kappa = 0.90, 95% CI 0.71– 1.00), in 83% cases for KRAS mutations (kappa = 0.67, 95% CI 0.54 – 0.80) and in 91% cases for PIK3CA mutations (kappa = 0.65, 95% CI 0.46 – 0.85). Patients (n = 41) with > 1% of KRAS mutant cfDNA had a shorter median survival compared to 20 patients with 1% of mutant cfDNA (BRAF, EGFR, KRAS, or PIK3CA) had a shorter median survival compared to 33 patients with
PMCID: PMC4494976  PMID: 25980577
EGFR; BRAF; KRAS; PIK3CA; cell-free DNA
Cell reports  2014;6(2):377-387.
Despite a wealth of preclinical studies, it is unclear whether PIK3CA or PTEN gene aberrations are actionable in the clinical setting. Of 1,656 patients with advanced, refractory cancers tested for PIK3CA or PTEN abnormalities, PIK3CA mutations were found in 9% (146/1,589), and PTEN loss and/or mutation in 13% (149/1,157). In multicovariable analysis, treatment with a PI3K/AKT/mTOR inhibitor was the only independent factor predicting response to therapy in individuals harboring a PIK3CA or PTEN aberration. The rate of stable disease (SD) ≥6 months/partial response reached 45% in a subgroup of individuals with H1047R PIK3CA mutations. Aberrations in the PI3K/AKT/mTOR pathway are common and potentially actionable in patients with diverse advanced cancers. This work provides further important clinical validation for continued and accelerated use of biomarker-driven trials incorporating rational drug combinations.
doi:10.1016/j.celrep.2013.12.035
PMCID: PMC4409143  PMID: 24440717
PIK3CA; PTEN; KRAS; NRAS; BRAF; Cancer; Clinical trial
Dermatology and Therapy  2015;5(2):129-143.
Introduction
Merkel cell carcinoma is a neuroendocrine malignancy. Suppressor of fused (SUFU) is a tumor suppressor oncogene that participates in the Hedgehog (Hh) signaling pathway. The aim of the study was to describe a patient whose Merkel cell carcinoma demonstrated a SUFU genomic alteration.
Case Study
The Hh signaling pathway is involved in the pathogenesis of several tumors, including nevoid basal cell carcinoma syndrome that is associated with an alteration of the patched-1 (PTCH1) gene. Targeted molecular therapy against smoothened (SMO) with vismodegib has been shown to be an effective therapeutic intervention for patients with PTCH-1 mutation. The reported patient was presented with metastatic Merkel cell carcinoma. Analysis of his tumor, using a next-generation sequencing-based assay, demonstrated a genomic aberration of SUFU protein, a component of the Hh signaling pathway that acts downstream to SMO and, therefore, is unlikely to be responsive to vismodegib. Of interest, arsenic trioxide or bromo and extra C-terminal inhibitors impact signals downstream to SUFU, making this aberration conceivably druggable. His tumor has initially been managed with chemotherapy (carboplatin and etoposide) and subsequent radiation therapy is planned.
Conclusion
The pathogenesis of Merkel cell carcinoma is multifactorial, and related to ultraviolet radiation exposure, immunosuppression, and Merkel cell polyomavirus. We report a patient with a mutation in SUFU, a potentially actionable component of the Hh signaling pathway.
Electronic supplementary material
The online version of this article (doi:10.1007/s13555-015-0074-5) contains supplementary material, which is available to authorized users.
doi:10.1007/s13555-015-0074-5
PMCID: PMC4470960  PMID: 25876211
Carcinoma; Cell; Hedgehog; Merkel; Pathway; Signaling; Suppressor of fused (SUFU)
Oncotarget  2015;6(8):6029-6039.
We hypothesized that aberrations activating epidermal growth factor receptor (EGFR) via dimerization would be more sensitive to anti-dimerization agents (e.g., cetuximab). EGFR exon 19 abnormalities (L747_A750del; deletes amino acids LREA) respond to reversible EGFR kinase inhibitors (TKIs). Exon 20 in-frame insertions and/or duplications (codons 767 to 774) and T790M mutations are clinically resistant to reversible/some irreversible TKIs. Their impact on protein function/therapeutic actionability are not fully elucidated.
In our study, the index patient with non-small cell lung cancer (NSCLC) harbored EGFR D770_P772del_insKG (exon 20). A twenty patient trial (NSCLC cohort) (cetuximab-based regimen) included two participants with EGFR TKI-resistant mutations ((i) exon 20 D770>GY; and (ii) exon 19 LREA plus exon 20 T790M mutations). Structural modeling predicted that EGFR exon 20 anomalies (D770_P772del_insKG and D770>GY), but not T790M mutations, stabilize the active dimer configuration by increasing the interaction between the kinase domains, hence sensitizing to an agent preventing dimerization. Consistent with predictions, the two patients harboring D770_P772del_insKG and D770>GY, respectively, responded to an EGFR antibody (cetuximab)-based regimen; the T790M-bearing patient showed no response to cetuximab combined with erlotinib. In silico modeling merits investigation of its ability to optimize therapeutic selection based on structural/functional implications of different aberrations within the same gene.
PMCID: PMC4467419  PMID: 25760241
EGFR; adenocarcinoma; lung cancer; reversible TKI inhibitors; irreversible TKI inhibitors
Clinical Epigenetics  2015;7(1):29.
Background
Demethylation process is necessary for the expression of various factors involved in chemotherapy cytotoxicity or resistance. Platinum-resistant cells may have reduced expression of the copper/platinum transporter CTR1. We hypothesized that azacitidine and oxaliplatin combination therapy may restore platinum sensitivity. We treated patients with cancer relapsed/refractory to any platinum compounds (3 + 3 study design) with azacitidine (20 to 50 mg/m2/day intravenously (IV) over 15 to 30 min, D1 to 5) and oxaliplatin (15 to 30 mg/m2/day, IV over 2 h, D2 to 5) (maximum, six cycles). Platinum content, LINE1 methylation (surrogate of global DNA methylation), and CTR1 expression changes (pre- vs. post-treatment) were assessed. Drug pharmacokinetics were analyzed.
Results
Thirty-seven patients were treated. No dose-limiting toxicity (DLT) was noted at the maximum dose. The most common adverse events were anemia and fatigue. Two (5.4%) patients had stable disease and completed six cycles of therapy. Oxaliplatin (D2) and azacitidine (D1 and 5) mean systemic exposure based on plasma AUCall showed dose-dependent interaction whereby increasing the dose of oxaliplatin reduced the mean azacitidine exposure and vice versa; however, no significant differences in other non-compartmental modeled parameters were observed. Blood samples showed universal reduction in global DNA methylation. In tumor samples, hypomethylation was only observed in four out of seven patients. No correlation between blood and tumor demethylation was seen. The mean cytoplasmic CTR1 score decreased. The pre-dose tumor oxaliplatin levels ranged from <0.25 to 5.8 μg/g tumor. The platinum concentration increased 3- to 18-fold. No correlation was found between CTR1 score and oxaliplatin level, which was found to have a trend toward correlation with progression-free survival.
Conclusions
Oxaliplatin and azacitidine combination therapy was safe. CTR1 expression was not correlated with methylation status or tissue platinum concentration.
Electronic supplementary material
The online version of this article (doi:10.1186/s13148-015-0065-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s13148-015-0065-5
PMCID: PMC4371799  PMID: 25806091
DNA methylation; Platinum resistance; Copper/platinum transporter
Oncotarget  2015;6(7):4553-4561.
Despite recent improvements, overall survival for advanced adenocarcinoma of the pancreas continues to be poor. In comparison to other tumor types that have enjoyed marked survival benefit by targeting aberrant cell signaling pathways, standard of care treatment for pancreatic cancer is limited to conventional cytotoxic chemotherapy. Multiple pathway aberrations have been documented in pancreatic cancer. A review of the COSMIC database reveals that most pancreatic cancers contain somatic mutations, with the five most frequent being KRAS, TP53, CDKN2A, SMAD4, and ARID1A, and multiple other abnormalities seen including, but not limited to, mutations in STK11/LKB1, FBXW7, PIK3CA, and BRAF. In the era of tumor profiling, these aberrations may provide an opportunity for new therapeutic approaches. Yet, searching clinicaltrials.gov for recent drug intervention trials for pancreatic adenocarcinoma, remarkably few (10 of 116 (8.6%)) new study protocols registered in the last three years included a molecular/biomarker stratification strategy. Enhanced efforts to target subsets of patients with pancreatic cancer in order to optimize therapy benefit are warranted.
PMCID: PMC4467098  PMID: 25714017
Pancreatic Cancer; Targeted Therapy; Biomarker Stratification
Head & neck  2013;36(3):E25-E27.
Background
Salivary ductal carcinoma is a rare cancer with poor prognosis and limited treatment options. HER2-directed treatment has been attempted in HER2-amplified or overexpressed salivary gland malignancies with limited success.
Methods
We report resolution of measurable disease and minimal residual disease in a patient with salivary duct cancer treated with trastuzumab, lapatinib, and bevacizumab, with treatment ongoing for more than two years.
Results
This treatment has been tolerated well except for grade 2 diarrhea and mucositis, which required a dose reduction of lapatinib to 1000 mg daily. The response observed was achieved in spite of receiving extensive prior therapy, including trastuzumab and/or chemotherapy for 20 months on which his tumors progressed.
Conclusions
The combination of trastuzumab, lapatinib, and bevacizumab may warrant investigation as a non-cytotoxic alternative for treatment of HER2-amplified or overexpressed salivary duct carcinoma and other HER2-amplified or overexpressed salivary gland tumors, particularly those not responsive to trastuzumab monotherapy.
doi:10.1002/hed.23429
PMCID: PMC3893310  PMID: 23852769
salivary duct carcinoma; trastuzumab; lapatinib; HER2; bevacizumab
Introduction
Multicentric Castleman’s disease is a rare lymphoproliferative disorder whose hallmark is atypical lymph node hyperplasia. Symptoms can include fever, splenomegaly, and abnormal blood cell counts. High levels of interleukin 6 (IL-6) are observed frequently in this disorder and are believed to drive the disease. Recently, therapies that target interleukin-6 or its receptor have been shown to be effective in Castleman’s disease.
Case presentation
We report the case of a 76-year-old Caucasian man with aggressive biopsy-proven Castleman’s disease who experienced pulmonary and lymph node involvement, as well as fever and weight loss. He was treated with siltuximab, a chimeric anti-interleukin-6 antibody. After 5 months, fluorodeoxyglucose positron emission tomography computed tomography scans showed marked improvement in his lungs, but worsening mediastinal disease, consistent with a mixed response. Biopsy of the mediastinal disease revealed lymphoplasmacytic infiltrate with non-caseating, ill-defined granulomas and scarring consistent with sarcoidosis. Prednisone 50mg by mouth daily was started, which was tapered to 2.0-5.0mg daily. Siltuximab was continued. A subsequent fluorodeoxyglucose positron emission tomography computed tomography scan showed near-complete resolution of lung and mediastinal disease, now ongoing for 3.5+ years without serious adverse events.
Conclusions
Lymphomas have previously been reported to coexist with sarcoidosis, albeit rarely, but there has been only a single previous case of this type with Castleman’s disease. Of importance, early recognition of the presence of sarcoidosis in our patient prevented discontinuation of siltuximab therapy due to “progression”. Our experience may also have broader implications in that it suggests that etiology of “mixed responses” should be confirmed by performing biopsies on the progressive tumor.
doi:10.1186/s13256-015-0517-8
PMCID: PMC4365524  PMID: 25884809
Interleukin 6; Mixed response; Multicentric Castleman’s disease; Siltuximab
Cancer Metastasis Reviews  2015;34(1):157-164.
Human epidermal growth factor receptor 2 (HER2) amplification/overexpression is an effective therapeutic target in breast and gastric cancer. Although HER2 positivity has been reported in other malignancies, previous studies generally focused on one cancer type, making it challenging to compare HER2 positivity across studies/malignancies. Herein, we examined 37,992 patient samples for HER2 expression (+/− amplification) in a single laboratory. All 37,992 patients were tested by immunohistochemistry (IHC); 21,642 of them were also examined for HER2 amplification with either fluorescent in situ hybridization (FISH) (11,670 patients) or chromogenic in situ hybridization (CISH) (9,972 patients); 18,262 patients had tumors other than breast or gastric cancer. All tissues were analyzed in a Clinical Laboratory Improvement Amendments (CLIA) laboratory (Caris Life Sciences) at the request of referring physicians. HER2 protein overexpression was found in 2.7 % of samples. Over-expressed HER2 was detected predominantly in malignancies of epithelial origin; for cancers derived from mesenchyme, neuroendocrine tissue, central nervous system, and kidney, HER2 expression and amplification were remarkably rare or non-existent. Bladder carcinomas, gallbladder, extrahepatic cholangiocarcinomas, cervical, uterine, and testicular cancers showed HER2 positivity rates of 12.4, 9.8, 6.3, 3.9, 3.0, and 2.4 %, respectively. HER2 overexpression and/or amplification is frequently found across tumor types. These observations may have significant therapeutic implications in cancers not traditionally thought to benefit from anti-HER2 therapies.
Electronic supplementary material
The online version of this article (doi:10.1007/s10555-015-9552-6) contains supplementary material, which is available to authorized users.
doi:10.1007/s10555-015-9552-6
PMCID: PMC4368842  PMID: 25712293
HER2 overexpression; Cancer; IHC; FISH; HER2 amplification
BMC Cancer  2015;15:61.
Background
Patients with BRAF mutation-positive advanced melanoma respond well to matched therapy with BRAF or MEK inhibitors, but often quickly develop resistance.
Methods
Tumor tissue from ten patients with advanced BRAF mutation-positive melanoma who achieved partial response (PR) or complete response (CR) on BRAF and/or MEK inhibitors was analyzed using next generation sequencing (NGS) assay. Genomic libraries were captured for 3230 exons in 182 cancer-related genes plus 37 introns from 14 genes often rearranged in cancer and sequenced to average median depth of 734X with 99% of bases covered >100X.
Results
Three of the ten patients (median number of prior therapies = 2) attained prolonged CR (duration = 23.6+ to 28.7+ months); seven patients achieved either a PR or a short-lived CR. One patient who achieved CR ongoing at 28.7+ months and had tissue available close to the time of initiating BRAF inhibitor therapy had only a BRAF mutation. Abnormalities in addition to BRAF mutation found in other patients included: mutations in NRAS, APC and NF1; amplifications in BRAF, aurora kinase A, MYC, MITF and MET; deletions in CDKN2A/B and PAX5; and, alterations in RB1 and ATM. Heterogeneity between patients and molecular evolution within patients was noted.
Conclusion
NGS identified potentially actionable DNA alterations that could account for resistance in patients with BRAF mutation-positive advanced melanoma who achieved a PR or CR but whose tumors later progressed. A subset of patients with advanced melanoma may harbor only a BRAF mutation and achieve a durable CR on BRAF pathway inhibitors.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-015-1029-z) contains supplementary material, which is available to authorized users.
doi:10.1186/s12885-015-1029-z
PMCID: PMC4340232  PMID: 25886620
BRAF mutation; Melanoma; Next generation sequencing; Resistance; Time to treatment failure
Oncotarget  2014;6(5):3033-3042.
Cyclin genes are key regulatory components of the cell cycle. With the development of new agents, cyclin-related genes are becoming increasingly important as they can be targeted. Yet, the biological implications of these alterations have not been fully studied. Clinical characteristics and outcome parameters were compared for patients harboring cyclin alterations versus not. CCN alterations were found in 13% of our population (50/392; all amplifications) and were associated with breast cancer (P < 0.0001), a higher median number of concomitant molecular alterations (P < 0.0001), and liver metastases (P = 0.046). Harboring a cyclin amplification was not associated with overall survival, the time to metastasis/recurrence, nor with the best progression-free survival. In a Cox regression model, gastrointestinal histology (P < 0.0001), PTEN (P < 0.0001), and CDK alterations (P = 0.041) had a significant association with poorer overall survival. CCN amplifications significantly correlated with alterations in FGF/FGFR family genes as well as in MET and ARFRP1. An extended correlation study shed light on a network of co-amplifications influenced in part by genes that were localized on the same amplicons. CCN amplifications are common across cancers and had distinctive biological associations. Customized combinations targeting the cyclin pathway as well as the extended co-amplification network may be necessary in order to address resistance mechanisms.
PMCID: PMC4413635  PMID: 25596748
cyclin; next generation sequencing; molecular profile; amplification; Cancer
Oncoscience  2014;1(7):522-530.
Background
Children (patients ≤ 18 years of age) are not usually included on pharmaceutical industry sponsored Phase I trials.
Methods
We reviewed the medical records of 40 patients ≤ 18 years treated in ≥ 1 phase I trial at MD Anderson.
Results
The median OS was 8.5 months (95% CI, 5.5–13.2 months). In the multivariate analysis, age ≥15 only predicted increased OS (P = 0.0065), and >3 prior therapies (P = 0.053) predicted decreased OS. The median PFS was 2.8 months (95% CI, 2.3–4.1 months). In the multivariate analysis, independent factors that predicted increased PFS were age ≥15 years (P < 0.001) and prior radiation therapy (P = 0.049); performance status >1 (P < 0.001) and >3 prior therapies (P = 0.002) predicted decreased PFS. RMH score ≥ 2 and MDACC score ≥ 3 were associated with decreased median OS (P = 0.029 and P = 0.031 respectively).
Conclusions
It is feasible to conduct phase I studies in pediatric patients based on adult protocols. In the era of targeted therapy more trials should allow pediatric patients earlier in the drug development especially if deemed safe in adults in early phase trials.
Translational Relevance
Most pharmaceutical industry sponsored trials exclude patients less than 18 years in phase I clinical trials. Even in the era of targeted therapy pediatric patients usually have to wait for most phases of trials to be completed in adults before being allowed to enroll in clinical trials of new therapies, even in the advanced metastatic and relapsed setting. Some investigator initiated phase 1 trials of combinations of US FDA approved agents allow patients less than 18 years. We report the preliminary analyses of the outcomes of pediatric patients enrolled in phase I studies initially designed for adults, but allowing for enrollment of patients under 18.
PMCID: PMC4278323  PMID: 25587555
phase I trials; children; prognostic scores; targeted therapy
British journal of haematology  2013;164(1):15-23.
We initially described the WHIM syndrome based on the combination of Warts, Hypogammaglobulinaemia, Infections and Myelokathexis (neutrophil retention in the bone marrow). Translational research led to the discovery that this rare immunodeficiency disease is caused by a heterozygous mutation in the CXCR4 gene. Recently, Plerixafor has been suggested as a treatment for WHIM syndrome due to its efficacy as a CXCR4 antagonist, closing the translational research loop. In this review, we will focus on the clinical manifestations, pathophysiology, diagnosis and possible therapies for this rare entity.
doi:10.1111/bjh.12574
PMCID: PMC3961560  PMID: 24111611
CXCR4; myelokathexis; neutropenia; plerixafor; WHIM
Oncotarget  2014;6(2):592-603.
Androgen receptors (ARs) play a critical role in the development of prostate cancer. Targeting ARs results in important salutary effects in this malignancy. Despite mounting evidence that ARs also participate in the pathogenesis and/or progression of diverse tumors, exploring the impact of hormonal manipulation of these receptors has not been widely pursued beyond prostate cancer. This review describes patterns of AR expression in a spectrum of cancers, and the potential to exploit this knowledge in the clinical therapeutic setting.
PMCID: PMC4359241  PMID: 25595907
androgen receptor; therapy; molecular abnormalities; phase I clinical trials
The Oncologist  2013;18(12):1315-1320.
This retrospective study was conducted to identify reasons that patients referred to a phase I clinical trial failed to enroll or delayed enrollment onto the trial. Approximately 55% of patients were enrolled on a phase I trial, and those referred from within MD Anderson were more likely to be enrolled than patients seen originally outside the institution. Major reasons for failure to enroll included failure to return to the clinic, opting for treatment in another clinic, hospice referral, early death, and lack of financial clearance.
Learning Objectives
Assess barriers for advanced cancer patients to participate in phase I trials.Discuss strategies to improve the rate of enrollment of cancer patients in phase I trials.
Background.
We conducted this retrospective study to identify reasons that patients referred to a phase I clinical trial failed to enroll or delayed enrollment onto the trial.
Materials and Methods.
Outcome analyses were conducted independently on data collected from electronic medical records of two sets of consecutive patients referred to a phase I clinical trial facility at MD Anderson Cancer Center. Data from the first set of 300 patients were used to determine relevant variables affecting enrollment; data from the second set of 957 patients were then analyzed for these variables.
Results.
Results from the two sets of patients were similar. Approximately 55% of patients were enrolled in a phase I trial. Patients referred from within MD Anderson were more likely to be enrolled than patients seen originally outside the institution (p = .006); black patients were more likely than white patients to enroll (69% vs. 43%; p = .04). The median interval from the initial visit to initiation of treatments was 19 days. Major reasons for failure to enroll included failure to return to the clinic (36%), opting for treatment in another clinic (17%), hospice referral (11%), early death (10%), and lack of financial clearance (5%). Treatment was delayed for three weeks or more in 250 patients; in 85 patients (34%), the delay was caused by financial and insurance issues.
Conclusion.
Failure to return to the clinic, pursuit of other therapy, and rapid deterioration were the major reasons for failure to enroll; lengthy financial clearance was the most common reason for delayed enrollment onto a phase I trial.
doi:10.1634/theoncologist.2013-0202
PMCID: PMC3868426  PMID: 24153239
Phase I trial; Enrollment; Consults; New patients; Patient referral; Barrier
Molecular cancer therapeutics  2013;12(12):2857-2863.
Target-matched treatment with PI3K/AKT/mTOR pathway inhibitors in patients with diverse advanced cancers with PIK3CA mutations have shown promise. Tumors from patients with colorectal cancer (CRC) were analyzed for PIK3CA, KRAS and BRAF mutations. PIK3CA mutated tumors were treated, whenever feasible, with agents targeting the PI3K/AKT/mTOR pathway. Of 194 patients analyzed, 31 (16%) had PIK3CA mutations, and 189 (97%) were assessed for KRAS mutations. Patients with PIK3CA mutations had a higher prevalence of simultaneous KRAS mutations than patients with wild-type (wt) PIK3CA (71%, 22/31 vs. 43%, 68/158; p=0.006). Of 31 patients with PIK3CA mutations, 17 (55%) were treated with protocols containing PI3K/AKT/mTOR pathway inhibitors (median age, 57; median number of prior therapies, 4; mTORC1 inhibitors [11], PI3K inhibitors [5] or an AKT inhibitor [1]). None (0/17) had a partial or complete response (PR/CR) and only 1 (6%, 95% CI 0.01–0.27) had stable disease (SD)≥6 months, which was not significantly different from a SD≥6 month/PR/CR rate of 16% (11/67; 95% CI 0.09–0.27) in CRC patients without PIK3CA mutations treated with PI3K/AKT/mTOR pathway inhibitors (p=0.44). Median progression-free survival was 1.9 months (95% CI 1.5–2.3). In conclusion, our data provide preliminary evidence that in heavily pretreated patients with PIK3CA-mutant advanced CRC, protocols incorporating PI3K/AKT/mTOR inhibitors have minimal activity. PIK3CA mutations are associated with simultaneous KRAS mutations, possibly accounting for therapeutic resistance.
doi:10.1158/1535-7163.MCT-13-0319-T
PMCID: PMC4158732  PMID: 24092809
PIK3CA mutation; PI3K/AKT/mTOR; Colorectal cancer; Target-matched therapy; KRAS mutation; Phase I trial
Journal of Personalized Medicine  2014;4(4):475-488.
Increasing efforts are being dedicated towards improving cancer care via personalized medicine. These efforts depend to a large degree on the availability of a knowledge foundation. Unfortunately, existing knowledge linking cancer drugs and potential efficacy biomarkers is in its infancy; and where links are known, they are frequently unstructured and poorly documented. We have developed a new open-access knowledgebase for precision cancer medicine (the PCM Wiki and Knowledgebase). This knowledgebase was constructed using an innovative, two-pronged approach involving a structured knowledgebase at the back-end, and an intuitive knowledge-sharing interface and user-friendly query engine in front. The knowledgebase was seeded with several patient case reports and information was mined via text-mining and literature review by human curators. Using our novel Wiki-based platform to present and share knowledge stored in the PCM knowledgebase, users are able to suggest corrections, propose additions or point to errors in the knowledgebase. The result is a community-driven evolving knowledgebase holding integrated and consolidated knowledge of markers and indications for personalized cancer medicine. We suggest that the PCM Knowledgebase and Wiki could serve as an important tool for the advancement of clinical trials and care in the field of precision cancer medicine.
doi:10.3390/jpm4040475
PMCID: PMC4282884  PMID: 25563458
cancer; case reports; genetics; knowledgebase; personalized medicine; precision medicine
Cancer chemotherapy and pharmacology  2013;72(5):1089-1096.
Purpose
Everolimus, an oral inhibitor of mTOR, can augment the efficacy of HER inhibitors in pre-clinical studies. This study was conducted to determine the safety and pharmacokinetics (PK) of the combination of lapatinib, a Her1 and 2 inhibitor, and everolimus, and to describe its antitumor activity in the Phase I setting.
Methods
In Part I, dose escalation to define the maximum tolerated dose (MTD) was performed. In Part II, PK of both drugs were analyzed to assess drug-drug interaction.
Results
Twenty-three evaluable patients with advanced cancers were treated on six different dose levels in Part I of the study. The dose-limiting toxicities were diarrhea, rash, mucositis and fatigue. The MTD of the combination was 1250 mg of lapatinib and 5 mg of everolimus once daily. In Part II of the study, 54 patients were treated with the combination at the MTD. The mean everolimus time to maximum concentration was increased by 44% and mean clearance was decreased by 25% when co-administered with lapatinib, though these differences were not statistically significant. There was no significant influence on the PK of lapatinib by everolimus. Two patients achieved a partial response (thymic cancer (45+ months) and breast cancer (unconfirmed PR; 7 months); eleven patients attained stable disease of at least 4 months
Conclusions
Lapatinib and everolimus are well tolerated at doses of 1250 mg and 5 mg po daily, respectively. Stable disease >4 months/PR was achieved in 13 of 78 patients (17%).
doi:10.1007/s00280-013-2297-4
PMCID: PMC4072025  PMID: 24057042
everolimus; lapatinib; phase I; mTOR; Her2
Oncotarget  2014;5(21):10280-10292.
Purpose
We hypothesized that bortezomib, an agent that suppresses HIF-1α transcriptional activity, when combined with bevacizumab, would obviate the HIF-1α resistance pathway. The objectives of this phase I trial were to assess safety and biological activity of this combination.
Experimental Design
Patients with advanced, refractory malignancies were eligible. Patients received bevacizumab and bortezomib (3-week cycle) with dose expansions permitted if responses were seen and for assessing correlates. Pharmacodynamic assessment included plasma VEGF, VEGFR2, 20S proteasome inhibition, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and HIF-1α tumor expression.
Results
Ninety-one patients were treated (median=6 prior treatments). The FDA-approved doses of both drugs were safely reached, and the recommended phase 2 dose (RP2D) is bevacizumab 15 mg/kg with bortezomib 1.3 mg/m2. Four patients attained partial response (PR) and seven patients achieved stable disease (SD) ≥6 months (Total SD≥6 months/PR=11 (12%)). The most common drug-related toxicities included thrombocytopenia (23%) and fatigue (19%). DCE-MRI analysis demonstrated no dose-dependent decreases in Ktrans although analysis was limited by small sample size (N=12).
Conclusion
Combination bevacizumab and bortezomib is well-tolerated and has demonstrated clinical activity in patients with previously treated advanced malignancy. Pharmacodynamic assessment suggests that inhibition of angiogenic activity was achieved.
PMCID: PMC4279372  PMID: 25373733
bevacizumab; bortezomib; phase 1; proteasome; HIF-1α

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