Ganessan Kichenadasse

Extended RAS mutations and anti-EGFR monoclonal antibody survival benefit in metastatic colorectal cancer: a meta-analysis of randomized, controlled trials

BACKGROUND Monoclonal antibodies (mAbs) targeting the epidermal growth factor receptor (EGFR) prolong survival in metastatic colorectal cancer (mCRC) Kirsten rat sarcoma viral oncogene (KRAS) exon 2 wild-type tumors. Recent evidence has suggested that other RAS mutations (in exons 3 and 4 of KRAS and exons 2, 3 and 4 of a related gene, NRAS) may also be predictive of resistance. METHODS Systematic review and meta-analysis of randomized, controlled trials (RCTs) evaluating anti-EGFR mAbs that have assessed tumors for new RAS mutations. Tumors with the new RAS mutations were compared with both tumors without any RAS mutations and tumors with KRAS exon 2 mutations with respect to anti-EGFR treatment progression-free survival (PFS) and overall survival (OS) benefit. RESULTS Nine RCTs comprising a total of 5948 participants evaluated for both KRAS exon 2 and new RAS mutations met the inclusion criteria. Approximately 20% of KRAS exon 2 wild-type tumors harbored one of the new RAS mutations. Tumors without any RAS mutations (either KRAS exon 2 or new RAS mutations) were found to have significantly superior anti-EGFR mAb PFS (P < 0.001) and OS (P = 0.008) treatment effect compared with tumors with any of the new RAS mutations. No difference in PFS or OS benefit was evident between tumors with KRAS exon 2 mutations and tumors with the new RAS mutations. Results were consistent between different anti-EGFR agents, lines of therapy and chemotherapy partners. Anti-EGFR mAb therapy significantly improved both PFS {hazard ratio 0.62 [95% confidence interval (CI) 0.50-0.76]} and OS [hazard ratio 0.87 (95% CI 0.77-0.99)] for tumors without any RAS mutations. No PFS or OS benefit was evident with use of anti-EGFR mAbs for tumors harboring any RAS mutation (P > 0.05). CONCLUSION Tumors harboring one of the new RAS mutations are unlikely to significantly benefit from anti-EGFR mAb therapy in mCRC.BACKGROUND Monoclonal antibodies (mAbs) targeting the epidermal growth factor receptor (EGFR) prolong survival in metastatic colorectal cancer (mCRC) Kirsten rat sarcoma viral oncogene (KRAS) exon 2 wild-type tumors. Recent evidence has suggested that other RAS mutations (in exons 3 and 4 of KRAS and exons 2, 3 and 4 of a related gene, NRAS) may also be predictive of resistance. METHODS Systematic review and meta-analysis of randomized, controlled trials (RCTs) evaluating anti-EGFR mAbs that have assessed tumors for new RAS mutations. Tumors with the new RAS mutations were compared with both tumors without any RAS mutations and tumors with KRAS exon 2 mutations with respect to anti-EGFR treatment progression-free survival (PFS) and overall survival (OS) benefit. RESULTS Nine RCTs comprising a total of 5948 participants evaluated for both KRAS exon 2 and new RAS mutations met the inclusion criteria. Approximately 20% of KRAS exon 2 wild-type tumors harbored one of the new RAS mutations. Tumors without any RAS mutations (either KRAS exon 2 or new RAS mutations) were found to have significantly superior anti-EGFR mAb PFS (P < 0.001) and OS (P = 0.008) treatment effect compared with tumors with any of the new RAS mutations. No difference in PFS or OS benefit was evident between tumors with KRAS exon 2 mutations and tumors with the new RAS mutations. Results were consistent between different anti-EGFR agents, lines of therapy and chemotherapy partners. Anti-EGFR mAb therapy significantly improved both PFS {hazard ratio 0.62 [95% confidence interval (CI) 0.50-0.76]} and OS [hazard ratio 0.87 (95% CI 0.77-0.99)] for tumors without any RAS mutations. No PFS or OS benefit was evident with use of anti-EGFR mAbs for tumors harboring any RAS mutation (P > 0.05). CONCLUSION Tumors harboring one of the new RAS mutations are unlikely to significantly benefit from anti-EGFR mAb therapy in mCRC.

Meta-analysis of BRAF mutation as a predictive biomarker of benefit from anti-EGFR monoclonal antibody therapy for RAS wild-type metastatic colorectal cancer

Metastatic colorectal cancer (mCRC) that harbours a BRAF V600E mutation (BRAF MT) is associated with poorer outcomes. However, whether this mutation is predictive of treatment benefit from anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) is uncertain. We conducted a systematic review and meta-analysis of randomised controlled trials (RCTs) published up to July 2014 that evaluated the effect of BRAF MT on the treatment benefit from anti-EGFR mAbs for mCRC. Seven RCTs met the inclusion criteria for assessment of overall survival (OS), whereas eight RCTs met the inclusion criteria for assessment of progression-free survival (PFS). For RAS WT/BRAF MT tumours, the hazard ratio for OS benefit with anti-EGFR mAbs was 0.97 (95% CI; 0.67–1.41), whereas the hazard ratio was 0.81 (95% CI; 0.70–0.95) for RAS WT/BRAF WT tumours. However, the test of interaction (P=0.43) was not statistically significant, highlighting that the observed differences in the effect of anti-EGFR mAbs on OS according to the BRAF mutation status may be due to chance alone. Regarding PFS benefit with anti-EGFR mAbs, the hazard ratio was 0.86 (95% CI; 0.61–1.21) for RAS WT/BRAF MT tumours as compared with 0.62 (95% CI; 0.50–0.77) for RAS WT/BRAF WT tumours (test of interaction, P=0.07). This meta-analysis demonstrates that there is insufficient evidence to definitively state that RAS WT/BRAF MT individuals attain a different treatment benefit from anti-EGFR mAbs for mCRC compared with RAS WT/BRAF WT individuals. As such, there are insufficient data to justify the exclusion of anti-EGFR mAb therapy for patients with RAS WT/BRAF MT mCRC.

Olanzapine for chemotherapy-induced nausea and vomiting: a systematic review

PurposeNewer drugs incorporated in prophylactic regimens for chemotherapy-induced nausea and vomiting (CINV) have resulted in significantly reduced rates of this feared complication of cytotoxic chemotherapy. However, both delayed chemotherapy-induced nausea and breakthrough CINV remain difficult areas of management and require novel treatment strategies. Recent randomized trial evidence has suggested that olanzapine, an atypical antipsychotic, may have a role in both the prevention and treatment of CINV. A systematic review was conducted to assess the efficacy of olanzapine in (a) preventing CINV in highly emetogenic chemotherapy (HEC) and moderately emetogenic chemotherapy (MEC) and (b) the treatment of breakthrough CINV. The toxicity of olanzapine in this setting was also reviewed.MethodsMEDLINE, Embase and Cochrane Database of Systematic Reviews databases were searched to identify all randomized clinical trials (RCTs) investigating olanzapine in patients receiving chemotherapy.ResultsA total of 488 patients from three trials of CINV prophylaxis and 323 patients from three trials of breakthrough CINV were included. Regimens including olanzapine were associated with significant improvements in CINV prevention with both HEC and MEC. Single agent olanzapine for breakthrough nausea was superior to standard alternative options.ConclusionData from RCTs support the use of an olanzapine containing combination regimen as an option for CINV prophylaxis and single agent olanzapine for the treatment of breakthrough CINV. In the included trials, the short duration of olanzapine appears safe and well tolerated.

Secondary Somatic Mutations Restoring RAD51C and RAD51D Associated with Acquired Resistance to the PARP Inhibitor Rucaparib in High-Grade Ovarian Carcinoma

High-grade epithelial ovarian carcinomas containing mutated BRCA1 or BRCA2 (BRCA1/2) homologous recombination (HR) genes are sensitive to platinum-based chemotherapy and PARP inhibitors (PARPi), while restoration of HR function due to secondary mutations in BRCA1/2 has been recognized as an important resistance mechanism. We sequenced core HR pathway genes in 12 pairs of pretreatment and postprogression tumor biopsy samples collected from patients in ARIEL2 Part 1, a phase II study of the PARPi rucaparib as treatment for platinum-sensitive, relapsed ovarian carcinoma. In 6 of 12 pretreatment biopsies, a truncation mutation in BRCA1, RAD51C, or RAD51D was identified. In five of six paired postprogression biopsies, one or more secondary mutations restored the open reading frame. Four distinct secondary mutations and spatial heterogeneity were observed for RAD51CIn vitro complementation assays and a patient-derived xenograft, as well as predictive molecular modeling, confirmed that resistance to rucaparib was associated with secondary mutations.Significance: Analyses of primary and secondary mutations in RAD51C and RAD51D provide evidence for these primary mutations in conferring PARPi sensitivity and secondary mutations as a mechanism of acquired PARPi resistance. PARPi resistance due to secondary mutations underpins the need for early delivery of PARPi therapy and for combination strategies. Cancer Discov; 7(9); 984-98. ©2017 AACR.See related commentary by Domchek, p. 937See related article by Quigley et al., p. 999See related article by Goodall et al., p. 1006This article is highlighted in the In This Issue feature, p. 920.

Accelerated BEP for metastatic germ cell tumours: a multicenter phase II trial by the Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP)

BACKGROUND This Australian single-arm, multicenter, phase II trial evaluated feasibility, tolerability and activity of accelerated bleomycin, etoposide and cisplatin (BEP) as first-line chemotherapy for metastatic germ cell tumours. PATIENTS AND METHODS Patients were planned to receive cisplatin 20 mg/m(2) and etoposide 100 mg/m(2) days 1-5, and pegfilgrastim 6 mg day 6, all repeated every 2 weeks for four cycles (three cycles for good prognosis). Bleomycin was given at 30 000 IU weekly to a total of 12 doses (9 doses for good prognosis). Primary end point was feasibility, defined as the proportion of patients able to complete the etoposide and cisplatin components of BEP and be eligible to receive a fourth cycle of BEP by day 50. RESULTS Twelve poor, 16 intermediate and 15 good prognosis (n = 43) eligible patients were enrolled. Two patients aged >40 years were ineligible and excluded from analyses. The regimen was feasible in 86%, not feasible in 7% and not assessable in 7% of patients. Most common grade 3/4 adverse events were non-neutropenic infection (16%) and febrile neutropenia (12%). Complete response (CR) to chemotherapy and surgery was achieved in 33% poor-prognosis, 81% intermediate-prognosis and 100% good-prognosis patients. At median follow-up of 27 months (range 6-42), the 2-year progression-free survival was 50% for poor-prognosis, 94% for intermediate-prognosis and 92% for good-prognosis patients. CONCLUSION Accelerated BEP is feasible and tolerable. Efficacy data appear to be promising. This trial and a similar UK study provide the rationale for a randomised trial comparing accelerated versus standard BEP. Australian New Zealand Clinical Trials Registry Registration number. ACTRN 12607000294459.

The emerging role of vascular endothelial growth factor (VEGF) in vascular homeostasis: lessons from recent trials with anti-VEGF drugs.

Vascular endothelial growth factor (VEGF) is an endogenous polypeptide that modulates angiogenesis in normal physiological conditions as well as in cancer. During angiogenesis, VEGF interacts with several other angiogenic factors, playing an important role in cell proliferation, differentiation, migration, cell survival, nitric oxide (NO) production, release of other growth factors and sympathetic innervation. Based on these mechanisms of action, several anti-VEGF drugs have been developed for cancer treatment. This review discusses the physiology and interactions of VEGF, its mechanisms of action and role in modulating vascular homeostasis. It also discusses the adverse cardiovascular effects of recently developed anti-VEGF drugs for the treatment of various types of cancer. A critical appraisal of the human studies on these drugs is provided. Furthermore, putative mechanisms for the onset of hypertension, the most common adverse cardiovascular effect, are discussed.

Non-vascular drug eluting stents as localized controlled drug delivery platform: Preclinical and clinical experience

Stents occupy an important place in the medical field for their widespread application. They have been used in vascular as well as in non-vascular organs for various reasons. Among vascular stents, development of coronary drug eluting stents (DESs) has completely revolutionised the percutaneous coronary intervention. Similarly, attempts have been made to make use of this modality in non-vascular organs. This paper focuses on the preclinical and clinical experience with drug-eluting non-vascular stents with emphasis on drug delivery systems and regulatory requirements for their development.

Inhibition of human UDP-glucuronosyltransferase enzymes by lapatinib, pazopanib, regorafenib and sorafenib: Implications for hyperbilirubinemia

Graphical abstract Figure. No Caption available. ABSTRACT Kinase inhibitors (KIs) are a rapidly expanding class of drugs used primarily for the treatment of cancer. Data relating to the inhibition of UDP‐glucuronosyltransferase (UGT) enzymes by KIs is sparse. However, lapatinib (LAP), pazopanib (PAZ), regorafenib (REG) and sorafenib (SOR) have been implicated in the development of hyperbilirubinemia in patients. This study aimed to characterise the role of UGT1A1 inhibition in hyperbilirubinemia and assess the broader potential of these drugs to perpetrate drug–drug interactions arising from UGT enzyme inhibition. Twelve recombinant human UGTs from subfamilies 1A and 2B were screened for inhibition by LAP, PAZ, REG and SOR. IC50 values for the inhibition of all UGT1A enzymes, except UGT1A3 and UGT1A4, by the four KIs were <10 &mgr;M. LAP, PAZ, REG and SOR inhibited UGT1A1‐catalysed bilirubin glucuronidation with mean IC50 values ranging from 34 nM (REG) to 3734 nM (PAZ). Subsequent kinetic experiments confirmed that REG and SOR were very potent inhibitors of human liver microsomal &bgr;‐estradiol glucuronidation, an established surrogate for bilirubin glucuronidation, with mean Ki values of 20 and 33 nM, respectively. Ki values for LAP and PAZ were approximately 1‐ and 2‐orders of magnitude higher than those for REG and SOR. REG and SOR were equipotent inhibitors of human liver microsomal UGT1A9 (mean Ki 678 nM). REG and SOR are the most potent inhibitors of a human UGT enzyme identified to date. In vitro–in vivo extrapolation indicates that inhibition of UGT1A1 contributes significantly to the hyperbilirubinemia observed in patients treated with REG and SOR, but not with LAP and PAZ. Inhibition of other UGT1A1 substrates in vivo is likely.

Meta-analysis comparing the efficacy of anti-EGFR monoclonal antibody therapy between KRAS G13D and other KRAS mutant metastatic colorectal cancer tumours

BACKGROUND Metastatic colorectal cancer (mCRC) tumours harbouring a RAS mutation are associated with a lack of treatment benefit from anti-EGFR monoclonal antibodies (mAbs). However, observational evidence has led to speculation that mCRC patients with KRAS G13D mutant (MT) tumours may derive a benefit from treatment with anti-EGFR mAbs. METHODS We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate whether the efficacy of anti-EGFR mAbs for mCRC differs between tumours harbouring a KRAS G13D mutation (KRAS G13D) and KRAS mutations other than G13D (other KRAS MT). RESULTS Eight RCTs (n = 5967) met the inclusion criteria for assessment of both overall survival (OS) and progression-free survival (PFS). For other KRAS MT the hazard ratio for OS benefit with addition of anti-EGFR mAb therapy was 1.06 (95% confidence interval [CI]; 0.96, 1.17), compared to 1.08 (95% CI; 0.73, 1.60) for KRAS G13D [test for interaction p=0.99]. In contrast, the hazard ratio for KRAS wild-type (WT) tumours was 0.85 (95% CI; 0.76, 0.95). Regarding PFS benefit with anti-EGFR mAbs, the hazard ratio was 1.07 (95% CI; 0.92, 1.26) for other KRAS MT, 0.96 (95% CI; 0.73, 1.27) for KRAS G13D, and 0.68 (95% CI; 0.54, 0.85) for KRAS WT. Again, the test for interaction (p=0.46) demonstrated no significant difference in PFS benefit for anti-EGFR mAb therapy between KRAS G13D and other KRAS MT. CONCLUSION This meta-analysis demonstrates no significant difference between KRAS G13D and other KRAS MT tumours in terms of treatment benefit from anti-EGFR mAbs for mCRC.

Gynecologic Cancer InterGroup (GCIG) consensus review for carcinoid tumors of the ovary.

Abstract Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms most commonly occurring in the gastrointestinal tract or the lungs. More frequent are gastrointestinal tumors, but over the past 30 years, there have been a number of small series or anecdotal case reports on ovarian NETs. Neuroendocrine tumors in the gynecologic tract are uncommon and account for about 2% of all gynecologic malignancies but may also be metastatic from other sites. They require a multimodality therapeutic approach determined by the extent of disease and the primary organ of involvement. Pathological diagnosis is critical to guide therapy. Surgery is the cornerstone of treatment for localized disease. There have been many new developments for treatment of advanced NETs including somatostatin analogs, hepatic artery embolization, chemotherapy, interferons, mammalian target of rapamycin inhibitors and radiolabeled somatostatin analogs. Given the rarity and lack of level I evidence, this is by nature more of a guidance and recommendation for management of these rare tumors until we can mount international studies.