No abstract

Immune checkpoints normally stop the body from mounting an immune response against healthy cells. Some cancers can acquire these checkpoints so that the tumour cells are not recognised by the immune system. Inhibiting the checkpoints therefore enables the tumour cells to be recognised and allows an immune response to be activated against them. Immune checkpoint inhibitors can improve the survival of some patients with advanced malignancies. These include malignant melanoma, renal cell carcinoma, urothelial bladder cancer and non-small cell lung cancer. Trials have shown that immune checkpoint inhibitors have significant benefits over conventional therapies so they are increasingly being used in routine clinical practice. However, a significant proportion of patients will not respond to immune checkpoint inhibitors and retain a poor prognosis. The optimal use of these drugs requires further study. Immune-related adverse events commonly include pneumonitis, hepatitis, nephritis, colitis and endocrinopathies. However, nearly any organ system can be affected. These toxicities present clinicians with a new challenge of recognising them early and acting promptly. the immune response is highly precise, as the receptor on the T cell is specific for one particular antigen. In addition to this antigen-specific binding, a 'second signal' is needed for T-cell activation. This involves co-stimulatory receptors such as CD28. The two-step process acts as a fail-safe, to prevent an inappropriate immune response causing damage to healthy tissues. If a second signal is not received, the T cells become anergic. Two pathways are central to the immune process: • cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) • programmed cell death 1 (PD-1) molecule. The CTLA-4 pathway is the best studied and its predominant role is as an immune dampener to prevent the initial activation of T cells in lymph nodes. PD-1 regulates the interaction of already activated T cells in extra-lymphatic tissues (see Fig.). 2 Highly mutant tumours are commonly able to acquire, or 'hijack' the immune checkpoints. This allows tumour cells to be inappropriately recognised as self tissues and so they restrain the T cell's ability to mount an effective antitumour response. The immune checkpoint inhibitors stop the inhibitory effects of tumour cells on T cells. By inhibiting the immune checkpoints, immune-mediated antitumour activity is restored.

Background The CHAARTED and STAMPEDE trials showed that the addition of docetaxel (D) to androgen deprivation therapy (ADT) prolonged longevity of men with metastatic hormone sensitive prostate cancer (mHSPC). However, the impact of upfront D on subsequent therapies is still unexplored. As abiraterone acetate (AA) and enzalutamide (E) are the most commonly used first-line treatment for metastatic CRPC (mCRPC), we aimed to assess whether they maintained their efficacy after ADT+D versus ADT alone. Patients and Methods A cohort of mCRPC patients treated between 2014 and 2017 with first-line AA or E for mCRPC was identified from three hospitals’ IRB approved databases. Patients were classified by use of D for mHSPC. This time frame was chosen as ADT+D became a valid therapeutic option for mHSPC in 2014 and it inherently entailed a short follow-up time on AA/E. The endpoints included overall survival (OS) from ADT start, OS from AA/E start, and time to AA/E start from ADT start. Differences between groups were assessed using the log-rank test. Results Of the 102 mCRPC patients identified, 50 (49%) had previously received ADT alone, while 52 (51%) had ADT+D. No statistically significant difference in any of the evaluated outcomes was observed between the 2 cohorts. Yet, deaths in the ADT+D group were 12 versus 21 in the ADT alone, after a median follow-up of 24.4 and 29.8 months, respectively. Conclusion In a cohort of ADT/ADT+D treated mCRPC patients with short times to first-line AA/E and follow-up, the efficacy of AA/E is similar regardless of previous use of D.

Taxane-based chemotherapy regimens are in widespread use as standard of care treatment for patients with early breast cancer, though rarely its use can be complicated by taxane-induced pneumonitis (TIP). While breast cancer is the most diagnosed cancer in women worldwide, TIP remains under-described in this setting. Key questions relate to its incidence, diagnosis and management, potential predictive biomarkers, and the balance between this life-threatening toxicity and curatively intended treatment. At a single Australian institution, 6 cases of TIP are identified among 132 patients treated with a paclitaxel-containing regimen for early breast cancer (4.55%, 95% confidence interval 1.69-9.63%). This review first outlines the presentation, management, and outcomes for these cases, then answers these questions and proposes an approach to suspected TIP in patients with breast cancer.