BRCA1 and BRCA2 carriers with breast, ovarian and prostate cancer demonstrate a different pattern of metastatic disease compared with non-carriers: results from a rapid autopsy programme.

AIM: To catalogue and compare the pattern of metastatic disease in germline BRCA1/2 pathogenic mutation carriers and non-carriers with breast, ovarian and prostate cancer from a rapid autopsy programme. METHODS AND RESULTS: The number of metastases in the major body systems and the proportion of participants with metastases were documented in 50 participants (19 germline mutation carriers). Analysis was conducted on the participants' pattern of disease for the different cancers and mutation subgroups. The four commonly affected organ systems were the digestive (liver only) (82%), respiratory (76%), gastrointestinal (65%) and reticuloendothelial (42%). There were significant differences in the pattern of metastatic breast cancer in BRCA1/2 germline carriers compared with non-carriers. Breast cancer carriers had significantly fewer organ systems involved (median n = 3, range = 1-3) compared with non-carriers (median n = 9, range = 1-7) (P = 0.03). BRCA1/2 carriers with ovarian carcinomas had significantly more organ systems with metastatic carcinoma (median n = 10, range = 3-8) than non-carriers (median n = 5, range = 3-5) (P < 0.001). There were no significant differences in the number of involved systems in BRCA2 carriers compared with non-carriers with prostate cancer (P = 1.0). There was an absence of locoregional disease (6.5%) compared with distant disease (93.5%) among the three cancer subtypes (P < 0.001). The majority of metastatic deposits (97%) collected during the autopsy were identified by recent diagnostic imaging. CONCLUSION: Even though a major limitation of this study is that our numbers are small, especially in the breast cancer carrier group, the metastatic patterns of breast and ovarian cancers may be impacted by BRCA1/2 carrier status, suggesting that tumours derived from patients with these mutations use different mechanisms of dissemination. The findings may focus clinical diagnostic imaging for monitoring metastases where whole-body imaging resources are scant.

Timing of whole genome duplication is associated with tumor-specific MHC-II depletion in serous ovarian cancer.

Whole genome duplication is frequently observed in cancer, and its prevalence in our prior analysis of end-stage, homologous recombination deficient high grade serous ovarian cancer (almost 80% of samples) supports the notion that whole genome duplication provides a fitness advantage under the selection pressure of therapy. Here, we therefore aim to identify potential therapeutic vulnerabilities in primary high grade serous ovarian cancer with whole genome duplication by assessing differentially expressed genes and pathways in 79 samples. We observe that MHC-II expression is lowest in tumors which have acquired whole genome duplication early in tumor evolution, and further demonstrate that reduced MHC-II expression occurs in subsets of tumor cells rather than in canonical antigen-presenting cells. Early whole genome duplication is also associated with worse patient survival outcomes. Our results suggest an association between the timing of whole genome duplication, MHC-II expression and clinical outcome in high grade serous ovarian cancer that warrants further investigation for therapeutic targeting.

Small-scale mutations are infrequent as mechanisms of resistance in post-PARP inhibitor tumour samples in high grade serous ovarian cancer.

While the introduction of poly-(ADP)-ribose polymerase (PARP) inhibitors in homologous recombination DNA repair (HR) deficient high grade serous ovarian, fallopian tube and primary peritoneal cancers (HGSC) has improved patient survival, resistance to PARP inhibitors frequently occurs. Preclinical and translational studies have identified multiple mechanisms of resistance; here we examined tumour samples collected from 26 women following treatment with PARP inhibitors as part of standard of care or their enrolment in clinical trials. Twenty-one had a germline or somatic BRCA1/2 mutation. We performed targeted sequencing of 63 genes involved in DNA repair processes or implicated in ovarian cancer resistance. We found that just three individuals had a small-scale mutation as a definitive resistance mechanism detected, having reversion mutations, while six had potential mechanisms of resistance detected, with alterations related to BRCA1 function and mutations in SHLD2. This study indicates that mutations in genes related to DNA repair are detected in a minority of HGSC patients as genetic mechanisms of resistance. Future research into resistance in HGSC should focus on copy number, transcriptional and epigenetic aberrations, and the contribution of the tumour microenvironment.

Multiomic analysis of homologous recombination-deficient end-stage high-grade serous ovarian cancer.

High-grade serous ovarian cancer (HGSC) is frequently characterized by homologous recombination (HR) DNA repair deficiency and, while most such tumors are sensitive to initial treatment, acquired resistance is common. We undertook a multiomics approach to interrogate molecular diversity in end-stage disease, using multiple autopsy samples collected from 15 women with HR-deficient HGSC. Patients had polyclonal disease, and several resistance mechanisms were identified within most patients, including reversion mutations and HR restoration by other means. We also observed frequent whole-genome duplication and global changes in immune composition with evidence of immune escape. This analysis highlights diverse evolutionary changes within HGSC that evade therapy and ultimately overwhelm individual patients.

New biomarkers for checkpoint inhibitor therapy.

Immune checkpoint inhibitor blockade has vastly changed treatment paradigms and improved outcomes of many solid organ malignancies. The achievements of the last decade have transformed the outcomes of several tumour types, most notably metastatic melanoma. There are, however, still large numbers of patients who receive checkpoint inhibitor therapy and do not respond. In addition to potential lack of efficacy, checkpoint inhibitors also come with a unique and sometimes devastating side-effect profile. There exists a strong need for biomarkers to accurately predict response, improve treatment selection and avoid exposing patients to toxicity where there is minimal likelihood of response. There is a wide range of methodologies investigating predictive biomarkers in this space; in this review, we address the major putative biomarkers of interest. These include conventional serum tests such as lymphocyte indices and lactate dehydrogenase, and more novel research markers such as interleukin-6 and T receptor clonality. We discuss tumorous factors that may be of interest in certain tumour types, and finally gene expression profiling. Significant research continues into many of these potential predictive biomarkers in response to the emergent need to better select patients who will benefit from treatment.

Cancer outcomes in patients requiring immunosuppression in addition to corticosteroids for immune-related adverse events after immune checkpoint inhibitor therapy.

AIM: To examine the cancer-specific outcomes for patients who experience immune-related adverse events requiring immunosuppression beyond corticosteroids. METHODS: We performed a retrospective case series of patients between January 1, 2009 and April 1, 2018, across three metropolitan hospitals in Adelaide, South Australia. Eligible patients were identified from pharmacy records. Patients with a solid organ malignancy had discontinued checkpoint inhibitor therapy due to toxicity, and required immunosuppression in addition to corticosteroids to treat any immune-related adverse event. RESULTS: From 3860 patient dispensation records of immunosuppressive medications, 19 eligible patients were identified. Eight received a CTLA-4 inhibitor, four a PD-1 inhibitor, five combination immunotherapy, and two remained blinded. Sixteen patients had melanoma and three had non-small cell lung cancer. Median time to treatment failure was 8.7 months, and median overall survival was 9.4 months. Of those evaluable, the objective response rate was 35%, while 53% had progressive disease. Four patients died due to complications of their irAE, while six died from progressive disease. CONCLUSION: Patients who received immunosuppression for checkpoint inhibitor therapy toxicity had variable outcomes. This in part reflects a heterogeneous population, and the evolution of irAE management over time. Several patients continued to derive a benefit after cessation of therapy despite the use of immunosuppressive medications; conversely, four died as a direct consequence of their irAE. Physicians should promptly introduce immunosuppressive therapy in patients not responding to corticosteroids to mitigate the risk of life-threatening adverse events, given that current evidence does not clearly demonstrate a detriment to cancer-specific outcomes.

Competing Risks in Older Patients With Cancer: A Systematic Review of Geriatric Oncology Trials.

Background: It is increasingly recognized that older adults with cancer represent a diverse cohort of patients and that other comorbidities may have an equal impact on survival and quality of life as any diagnosis of malignancy. Competing risk has consequently emerged as an important concept in the design and reporting of geriatric oncology trials. Methods: We performed a systematic review of phase II and III oncology trials for systemic therapy in older patients with solid organ malignancy from the year 2000 until April 30, 2017. Forty-one trials including 7864 patients were identified for evaluation. Results: Only 15 trials (36.6%) employed disease-related end points to account for death from other causes, and only one study used statistical analysis that addressed competing risk. Seventeen studies (41.5%) of trials included some assessment of comorbidity or frailty. Twenty-one trials (51.2%) included any assessment of quality of life. Conclusions: This review demonstrates clear areas for improvement for future studies and highlights the need for careful consideration of trial design, data collection, and appropriate statistical methodology for reporting of competing risks in geriatric oncology trials.

Video-assisted thoracoscopy in the management of intrapleural extravasation of cytotoxic chemotherapy.

The extravasation of cytotoxic agents into subcutaneous tissue is a serious complication of chemotherapy. Unfortunately, if such extravasation occurs into the pleural space, limited data is available to guide appropriate management. We present the first report in the literature of video-assisted thoracoscopy combined with a topoisomerase II inhibitor and iron chelator, dexrazoxane, in the successful management of this complication.

Difficulties with assessing the benefit of glucosamine sulphate as a treatment for osteoarthritis.

Osteoarthritis is a chronic disease with a major impact on quality of life for a large proportion of the population. It is a disease for which to date there has been no disease-modifying therapy identified. As a result of its physiological role in articular cartilage, glucosamine sulphate has been postulated as a treatment for osteoarthritis. Claims have included symptomatic relief and even reduction in the rate of disease progression. Despite promising in vitro studies, however, the role of glucosamine sulphate in the management of osteoarthritis remains unclear. Studies addressing this issue have generated a wide range of conclusions, and these are discussed here. Methodological issues need to be addressed in order to gauge whether there is true benefit. On current evidence, it would appear that the benefits of dietary supplementation with glucosamine sulphate are limited to mild symptomatic relief, while a disease-modifying agent for this disease remains elusive.