CA : A Cancer Journal for Clinicians

Major international projects are underway that are aimed at creating a comprehensive catalogue of all the genes responsible for the initiation and progression of cancer. These studies involve the sequencing of matched tumour-normal samples followed by mathematical analysis to identify those genes in which mutations occur more frequently than expected by random chance. Here we describe a fundamental problem with cancer genome studies: as the sample size increases, the list of putatively significant genes produced by current analytical methods burgeons into the hundreds. The list includes many implausible genes (such as those encoding olfactory receptors and the muscle protein titin), suggesting extensive false-positive findings that overshadow true driver events. We show that this problem stems largely from mutational heterogeneity and provide a novel analytical methodology, MutSigCV, for resolving the problem. We apply MutSigCV to exome sequences from 3,083 tumour-normal pairs and discover extraordinary variation in mutation frequency and spectrum within cancer types, which sheds light on mutational processes and disease aetiology, and in mutation frequency across the genome, which is strongly correlated with DNA replication timing and also with transcriptional activity. By incorporating mutational heterogeneity into the analyses, MutSigCV is able to eliminate most of the apparent artefactual findings and enable the identification of genes truly associated with cancer.

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Mutational heterogeneity in cancer and the search for new cancer-associated genes

Methods We conducted a multicenter, phase 1, dose-escalation trial of PLX4032 (also known as RG7204), an orally available inhibitor of mutated BRAF, followed by an extension phase involving the maximum dose that could be administered without adverse effects (the recommended phase 2 dose). Patients received PLX4032 twice daily until they had disease progression. Pharmacokinetic analysis and tumor-response assessments were conducted in all patients. In selected patients, tumor biopsy was performed before and during treatment to validate BRAF inhibition. Results A total of 55 patients (49 of whom had melanoma) were enrolled in the dose-escalation phase, and 32 additional patients with metastatic melanoma who had BRAF with the V600E mutation were enrolled in the extension phase. The recommended phase 2 dose was 960 mg twice daily, with increases in the dose limited by grade 2 or 3 rash, fatigue, and arthralgia. In the dose-escalation cohort, among the 16 patients with melanoma whose tumors carried the V600E BRAF mutation and who were receiving 240 mg or more of PLX4032 twice daily, 10 had a partial response and 1 had a complete response. Among the 32 patients in the extension cohort, 24 had a partial response and 2 had a complete response. The estimated median progression-free survival among all patients was more than 7 months. Conclusions Treatment of metastatic melanoma with PLX4032 in patients with tumors that carry the V600E BRAF mutation resulted in complete or partial tumor regression in the majority of patients. (Funded by Plexxikon and Roche Pharmaceuticals.)

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Inhibition of mutated, activated BRAF in metastatic melanoma.

Integrative genomic profiling of human prostate cancer

All cancers arise as a result of changes that have occurred in the DNA sequence of the genomes of cancer cells. Over the past quarter of a century much has been learnt about these mutations and the abnormal genes that operate in human cancers. We are now, however, moving into an era in which it will be possible to obtain the complete DNA sequence of large numbers of cancer genomes. These studies will provide us with a detailed and comprehensive perspective on how individual cancers have developed.

The cancer genome

The present invention relates to micellar nanocomplexes and a method of forming the same. The micellar nanocomplex comprises a micelle and an agent encapsulated within said micelle, where the micelle comprises a polymer-flavonoid conjugate, wherein said polymer is bonded to the B ring of said flavonoid. The micellar nanocomplex may have useful applications as a drug-delivery system.

A micellar nanocomplex

4555 Background: In mRCC pts who fail first-line VEGF-targeted therapy, there are no available randomized data comparing active drugs. Currently, many clinicians choose a second-line VEGF-targeted therapy based on the type of response to first-line VEGF therapy, although no data exists to support this practice. Methods: Pts treated with targeted therapy in the International mRCC Database Consortium were examined to identify pts who received a second-line VEGF-targeted therapy after failure of a different first-line VEGF-targeted therapy. Response rates and progression-free survival (PFS) were compared in the first- and second-line settings. Results: Of 1,602 total database pts, 464 pts received second-line VEGF-targeted therapy (sunitinib 37%, sorafenib 51%, axitinib 2%, bevacizumab 7%, pazopanib 3%) after failure of first-line VEGF-targeted therapy (sunitinib 54%, sorafenib 33%, bevacizumab 13%). The median overall survival from initiation of first-line therapy for pts who received second-line therapy wa...

The association of clinical outcome to front-line VEGF-targeted therapy with clinical outcome to second-line VEGF-targeted therapy in metastatic renal cell carcinoma (mRCC) patients (Pts).

Sunitinib commonly exhibits dose-limiting dermatological toxicities (DTs) that adversely affect health-related quality of life (HRQoL). Pharmacological activity of sunitinib is attributed to sunitinib and an equipotent, active metabolite, SU12662. The objective of this study is to compare the dermatotoxic potential of sunitinib and SU12662, and changes in HRQoL due to DTs. A prospective cohort study was conducted on metastatic renal cell carcinoma patients. Plasma drug concentrations were determined by high-performance liquid chromatography. DTs were graded by Common Terminology Criteria for Adverse Events. HRQoL of patients with hand–foot skin reaction (HFSR) was assessed by the hand–foot syndrome-specific quality-of-life questionnaire (HFS-14). In addition, the IC50s of both compounds were determined with HaCaT keratinocytes. Sunitinib was more dermatotoxic in vitro, with a lower IC50 than SU12662 (23.33 vs. 35.32 μM, p = 0.02). Similar results were observed in vivo, with higher sunitinib-to-SU12662 ratio in patients with pruritus, than patients without pruritus (p = 0.04). Higher HFS-14 scores were observed in patients with higher HFSR grade and in those with both hands and feet affected, indicating poorer HRQoL. Sunitinib may be more dermatotoxic than SU12662 from both in vivo and in vitro evidences. Therefore, appropriate management of DTs may be essential, especially in patients with a reduced sunitinib metabolising ability.

Role of sunitinib and SU12662 on dermatological toxicities in metastatic renal cell carcinoma patients: in vitro, in vivo, and outcomes investigation.

Reproductive factors, obesity and risk of colorectal cancer in a cohort of Asian women

The aim of this study was to assess associations of breastfeeding, adiposity and reproductive risk factors with ovarian cancer risk in a Singaporean population In addition to the main analysis, interaction effects of parity on other risk factors were examined A retrospective cohort consisting of 28,201 women with 107 incident ovarian cancers in up to 17 years of follow-up from the Singapore Breast Cancer Screening Project (1994–1997) was studied Hazard ratios (HRs) for risk factors were estimated using Cox proportional hazards models Body mass index and breastfeeding were found to have no statistical significant association with ovarian cancer risk Gravidity was inversely associated with ovarian cancer risk [each pregnancy, adjusted HR 089, 95 % confidence interval (CI) 081, 097], while results for parity were very similar (per delivery, HR 089, 95 % CI 081, 098) Each additional year of ovulatory period was found to increase ovarian cancer risk by 2 % (HR 102, 95 % CI 100, 104) Each year increase in total duration of oral contraceptive use reduced ovarian cancer risk by 6 % (HR 094, 95 % CI 085, 102) Parity, gravidity and shorter ovulatory period were associated with lower ovarian cancer risk Breastfeeding and body mass index were not associated with ovarian cancer risk, while increased duration of oral contraceptive use resulted in borderline risk reduction No significant evidence was found to suggest that parity had an interaction effect on any risk factor

Min-Han Tan

Papers

A micellar nanocomplex

The association of clinical outcome to front-line VEGF-targeted therapy with clinical outcome to second-line VEGF-targeted therapy in metastatic renal cell carcinoma (mRCC) patients (Pts).

Role of sunitinib and SU12662 on dermatological toxicities in metastatic renal cell carcinoma patients: in vitro, in vivo, and outcomes investigation.

Reproductive factors, obesity and risk of colorectal cancer in a cohort of Asian women

Reproductive factors, adiposity, breastfeeding and their associations with ovarian cancer in an Asian cohort