Adjuvant therapy in renal cell carcinoma

Publication date: Available online 23 September 2017
Source:Cancer Treatment Reviews
Author(s): Francesco Massari, Vincenzo Di Nunno, Chiara Ciccarese, Jeffrey Graham, Camillo Porta, Francesca Comito, Marta Cubelli, Roberto Iacovelli, Daniel Y.C. Heng
Several drugs have demonstrated clinical activity in metastatic renal cell carcinoma (mRCC). The identification of key metabolic pathways has led to the development of novel targeted therapies which have drastically changed the treatment paradigm of mRCC. Moreover, immune-checkpoint inhibitors have recently shown significant activity in advanced disease. Despite these advancements, the role of adjuvant therapy in localized, non-metastatic RCC remains unclear. The utility of many of these agents in the adjuvant setting is currently being actively explored. In this review, we will summarize the main clinical trials investigating adjuvant therapy in renal cell carcinoma, focusing primarily on immunotherapy and targeted agents.



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Patterns and the Occurrence of KRAS Mutations in Metastatic Colorectal Cancers—a Study from Indian Regional Cancer Centre

Abstract

Mutation analysis of the KRAS oncogene is established as a predictive biomarker in Colorectal cancer (CRC). Many prospective clinical trials have shown that only CRCs with wild-type KRAS respond to anti-epidermal growth factor receptor (EGFR) treatment. Hence, mutation analysis is mandatory before treatment of metastatic CRCs. There are very few studies on the KRAS mutation status in the Indian setting. Hence, this study was done to document the patterns of KRAS mutations in CRCs reporting to a regional cancer centre in South India. Among 150 cases of metastatic colorectal cancer reporting over a period of 20 months, 48 random cases were analyzed for the KRAS mutational status of codons 12 and 13 of the KRAS gene by genomic sequencing. KRAS mutations in codons 12 and 13 were present in 9/48 (18.75%) of all analyzed CRCs. The common types of mutations were glycine to aspartate on codon 12 (p.G12D), glycine to valine on codon 12 (p.G12 V), and glycine to aspartate on codon 13 (p.G13D).

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Patterns and the Occurrence of KRAS Mutations in Metastatic Colorectal Cancers—a Study from Indian Regional Cancer Centre

Abstract

Mutation analysis of the KRAS oncogene is established as a predictive biomarker in Colorectal cancer (CRC). Many prospective clinical trials have shown that only CRCs with wild-type KRAS respond to anti-epidermal growth factor receptor (EGFR) treatment. Hence, mutation analysis is mandatory before treatment of metastatic CRCs. There are very few studies on the KRAS mutation status in the Indian setting. Hence, this study was done to document the patterns of KRAS mutations in CRCs reporting to a regional cancer centre in South India. Among 150 cases of metastatic colorectal cancer reporting over a period of 20 months, 48 random cases were analyzed for the KRAS mutational status of codons 12 and 13 of the KRAS gene by genomic sequencing. KRAS mutations in codons 12 and 13 were present in 9/48 (18.75%) of all analyzed CRCs. The common types of mutations were glycine to aspartate on codon 12 (p.G12D), glycine to valine on codon 12 (p.G12 V), and glycine to aspartate on codon 13 (p.G13D).

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An atypical presentation of cardiac tamponade and periorbital swelling in a patient with eosinophilic granulomatosis with polyangiitis: a case report

Eosinophilic granulomatosis with polyangiitis is a rare, necrotizing systemic vasculitis associated with asthma and hypereosinophilia. Its cause and pathophysiology are still being elucidated.

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Genomic signatures as predictive biomarkers of homologous recombination deficiency in ovarian cancer

Publication date: November 2017
Source:European Journal of Cancer, Volume 86
Author(s): Adriaan Vanderstichele, Pieter Busschaert, Siel Olbrecht, Diether Lambrechts, Ignace Vergote
DNA repair deficiency is a common hallmark of many cancers and is increasingly recognised as a target for cancer therapeutics. Selecting patients for these treatments requires a functional assessment of multiple redundant DNA repair pathways. With the advent of whole-genome sequencing of cancer genomes, it is increasingly recognised that multiple signatures of mutational and chromosomal alterations can be correlated with specific DNA repair defects. The clinical relevance of this approach is underlined by the use of poly-(ADP-ribose) polymerase inhibitors (PARPi) in homologous recombination (HR) deficient high-grade serous ovarian cancers. Beyond deleterious mutations in HR-related genes such as BRCA1/2, it is recognised that HR deficiency endows ovarian cancers with specific signatures of base substitutions and structural chromosomal variation. Multiple metrics quantifying loss-of-heterozygosity (LOH) events were proposed and implemented in trials with PARPi. However, it was shown that some of the HR-deficient cases, i.e. CDK12–mutated tumours, were not associated with high LOH-based scores, but with distinct patterns of genomic alterations such as tandem duplication. Therefore, more complex signatures of structural genomic variation were identified and quantified. Ultimately, optimal prediction models for treatments targeting DNA repair will need to integrate multiples of these genomic signatures and will also need to assess multiple resistance mechanisms such as genomic reversion events that partially or fully re-activate DNA repair.



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PIKHER2: A phase IB study evaluating buparlisib in combination with lapatinib in trastuzumab-resistant HER2-positive advanced breast cancer

Publication date: November 2017
Source:European Journal of Cancer, Volume 86
Author(s): Mathilde Guerin, Keyvan Rezai, Nicolas Isambert, Mario Campone, Aurélie Autret, Jihane Pakradouni, Magali Provansal, Jacques Camerlo, Renaud Sabatier, François Bertucci, Emmanuelle Charafe-Jauffret, Alice Hervieu, Jean-Marc Extra, Patrice Viens, François Lokiec, Jean-Marie Boher, Anthony Gonçalves
BackgroundPhosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin pathway is frequently activated in HER2-positive breast cancer and may play a major role in resistance to trastuzumab. Buparlisib is a pan-class-I PI3K inhibitor with potent and selective activity against wild-type and mutant PI3K p110 isoforms.Patients and methodsPIKHER2 phase IB study aimed primarily to determine a maximum tolerated dose (MTD) and propose a recommended phase II dose (RP2D) for buparlisib in combination with lapatinib in HER2-positive, trastuzumab-resistant, advanced breast cancer. Oral buparlisib (40, 60 or 80 mg) and lapatinib (750, 1000 or 1250 mg) were administered daily. A modified continuous reassessment method using an adaptive Bayesian model guided the dose escalation of both agents. Secondary end-points included antitumour activity and pharmacokinetic (PK) assessments.ResultsA total of 24 patients were treated across five dose levels. Dose-limiting toxicities included transaminases elevation, vomiting, stomatitis, hyperglycemia and diarrhoea. MTD was declared at buparlisib 80 mg/d + lapatinib 1250 mg/d, but toxicities and early treatment discontinuation rate beyond cycle 1 led to select buparlisib 80 mg + lapatinib 1000 mg/d as the RP2D. Main drug-related adverse events included diarrhoea, nausea, skin rash, asthenia, depression, anxiety and transaminases increase. There was no significant evidence for drug–drug PK interaction. Disease control rate was 79% [95% confidence interval [CI] 57–92%], one patient obtained a complete remission, and six additional patients experienced stable disease for ≥ 24 weeks (clinical benefit rate of 29% [95% CI 12–51%]).ConclusionCombining buparlisib and lapatinib in HER2-positive trastuzumab-resistant advanced breast cancer was feasible. Preliminary evidence of antitumour activity was observed in this heavily pre-treated population.Trial registration IDNCT01589861.



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Determination of poor prognostic immune features of tumour microenvironment in non-smoking patients with lung adenocarcinoma

Publication date: November 2017
Source:European Journal of Cancer, Volume 86
Author(s): Tomonari Kinoshita, Chie Kudo-Saito, Reiko Muramatsu, Tomonobu Fujita, Miyuki Saito, Haruna Nagumo, Toshiharu Sakurai, Shinobu Noji, Emi Takahata, Tomonori Yaguchi, Nobuo Tsukamoto, Yuichiro Hayashi, Kaoru Kaseda, Ikuo Kamiyama, Takashi Ohtsuka, Kenji Tomizawa, Masaki Shimoji, Tetsuya Mitsudomi, Hisao Asamura, Yutaka Kawakami
We have previously demonstrated that the prognostic significance of tumour-infiltrating CD8⁺ T cells significantly differs according to histological type and patient smoking habits in non-small cell lung cancer (NSCLC). This work suggested that infiltrating CD8⁺ T cells may not be activated sufficiently in the immunosuppressive microenvironment in non-smokers with adenocarcinoma. To understand the immunogenic microenvironment in NSCLC, we characterised immune cells comprehensively by performing an immunohistochemical evaluation using an alternative counting method and multicolour staining method (n = 234), and assessed immune-related gene expression by using genetic analytical approaches (n = 58). We found that high infiltration of activated CD8⁺ T cells expressing interferon gamma (IFN-γ) and granzyme was correlated with postoperative survival in patients with non-adenocarcinoma. On the contrary, CD8⁺ T-cell accumulation was identified as a worse prognostic factor in patients with adenocarcinoma, particularly in non-smokers. Infiltrating CD8⁺ T cells were significantly less activated in this microenvironment with high expression of various immunoregulation genes. Potentially immunoregulatory CD8⁺ FOXP3⁺ T cells and immunodysfunctional CD8⁺ GATA3⁺ T cells were increased in adenocarcinoma of non-smokers. CD4⁺ FOXP3⁺ regulatory T cells expressing chemokine receptor-4 (CCR4)- and chemokine ligand (CCL17)-expressing CD163⁺ M2-like macrophages also accumulated correlatively and significantly in adenocarcinoma of non-smokers. These characteristic immune cells may promote tumour progression possibly by creating an immunosuppressive microenvironment in non-smoking patients with lung adenocarcinoma. Our findings may be helpful for refining the current strategy of personalised immunotherapy including immune-checkpoint blockade therapy for NSCLC.



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