Immune Activation following Irbesartan Treatment in a Colorectal Cancer Patient: A Case Study.

Colorectal cancers are one of the most prevalent tumour types worldwide and, despite the emergence of targeted and biologic therapies, have among the highest mortality rates. The Personalized OncoGenomics (POG) program at BC Cancer performs whole genome and transcriptome analysis (WGTA) to identify specific alterations in an individual's cancer that may be most effectively targeted. Informed using WGTA, a patient with advanced mismatch repair-deficient colorectal cancer was treated with the antihypertensive drug irbesartan and experienced a profound and durable response. We describe the subsequent relapse of this patient and potential mechanisms of response using WGTA and multiplex immunohistochemistry (m-IHC) profiling of biopsies before and after treatment from the same metastatic site of the L3 spine. We did not observe marked differences in the genomic landscape before and after treatment. Analyses revealed an increase in immune signalling and infiltrating immune cells, particularly CD8+ T cells, in the relapsed tumour. These results indicate that the observed anti-tumour response to irbesartan may have been due to an activated immune response. Determining whether there may be other cancer contexts in which irbesartan may be similarly valuable will require additional studies.

Whole-genome and transcriptome analysis enhances precision cancer treatment options.

BACKGROUND: Recent advances are enabling delivery of precision genomic medicine to cancer clinics. While the majority of approaches profile panels of selected genes or hotspot regions, comprehensive data provided by whole-genome and transcriptome sequencing and analysis (WGTA) present an opportunity to align a much larger proportion of patients to therapies. PATIENTS AND METHODS: Samples from 570 patients with advanced or metastatic cancer of diverse types enrolled in the Personalized OncoGenomics (POG) program underwent WGTA. DNA-based data, including mutations, copy number and mutation signatures, were combined with RNA-based data, including gene expression and fusions, to generate comprehensive WGTA profiles. A multidisciplinary molecular tumour board used WGTA profiles to identify and prioritize clinically actionable alterations and inform therapy. Patient responses to WGTA-informed therapies were collected. RESULTS: Clinically actionable targets were identified for 83% of patients, of which 37% of patients received WGTA-informed treatments. RNA expression data were particularly informative, contributing to 67% of WGTA-informed treatments; 25% of treatments were informed by RNA expression alone. Of a total 248 WGTA-informed treatments, 46% resulted in clinical benefit. RNA expression data were comparable to DNA-based mutation and copy number data in aligning to clinically beneficial treatments. Genome signatures also guided therapeutics including platinum, poly-ADP ribose polymerase inhibitors and immunotherapies. Patients accessed WGTA-informed treatments through clinical trials (19%), off-label use (35%) and as standard therapies (46%) including those which would not otherwise have been the next choice of therapy, demonstrating the utility of genomic information to direct use of chemotherapies as well as targeted therapies. CONCLUSIONS: Integrating RNA expression and genome data illuminated treatment options that resulted in 46% of treated patients experiencing positive clinical benefit, supporting the use of comprehensive WGTA profiling in clinical cancer care.

A review of post-trachelectomy isthmic and vaginal smear cytology.

Currently in the UK cervical cancer has a peak incidence in women aged 35-39. Fertility-conserving surgical treatment by radical trachelectomy is established in the management of early disease. This study aimed at establishing the value of cytology in follow-up after trachelectomy. The cytological features of isthmic-vaginal smears post-trachelectomy for cervical cancer are presented together with a discussion of relevant clinical issues. One hundred and ninety seven smears from 32 women were reviewed. Two of the 32 patients developed pelvic recurrences. In both cases recurrence was detected cytologically long before development of a clinical or radiological abnormality. There is, however, a potential for overcall due to the presence of endometrial cells. These were present in large numbers and varying configurations in 58% of smears and led to a false positive report of malignancy in 2% of smears. The rate of referral for a cytologist opinion was significantly higher in smears containing endometrial cells (26%) than those without (13%). While all smears contained squamous cells, 41% contained squamous cells only and it is proposed that such smears should be reported as unsatisfactory in the first 2 years after surgery and negative thereafter, although the absence of glandular cells should be recorded. When an abnormality is reported, smear review and multidisciplinary discussion may avoid unnecessary investigations.

Evaluation of 40 x 22 mm coverslip area in cervical cancer screening.

Nine hundred and twenty-three smears covered by 40 x 22 mm size coverslips were examined inside and outside the coverslip area to determine whether this coverslip size could be responsible for missed dyskaryotic cells in conventional cervical cancer screening. There was no instance when abnormal cells seen outside the coverslip were not also present within the coverslipped area.