Integrating immunotherapy in the (neo)adjuvant setting of early breast cancer.

PURPOSE OF REVIEW: Breast cancer is a relative latecomer in the success story of immuno-oncology. In this review, we focus on the preclinical and clinical lines of evidence to justify the evaluation of immune checkpoint inhibition (ICI) for the curative-intent treatment of breast cancer, the latest and ongoing trials of (neo)adjuvant immunotherapy, and practical considerations in clinical practice associated with this new treatment paradigm. RECENT FINDINGS: Insights from the immunobiology of breast cancer have paved the way for the new frontier of immunotherapy in this malignancy, starting from advanced stages and moving onto curable cases. Tumor-infiltrating lymphocyte quantification and PD-L1 immunohistochemistry are forerunners of predictive biomarkers for sensitivity to ICI in breast cancers. Preliminary results from phase III trials of combinatorial immunochemotherapy to treat early high-risk or locally advanced triple-negative breast cancer are encouraging for pathological complete response. Additional efficacy and patient-reported outcomes of (neo)adjuvant immunochemotherapy trials are awaited. SUMMARY: The prospect of integrating ICI in the treatment of early-stage breast cancer is promising. Questions regarding patient selection, the choice of ICI agent and combination partner in escalation strategies, sequencing and duration of treatments, cost-effectiveness and mechanisms of resistance remain to be answered by future research.

A phase 1 study of the safety, pharmacokinetics and pharmacodynamics of escalating doses followed by dose expansion of the selective inhibitor of nuclear export (SINE) selinexor in Asian patients with advanced or metastatic malignancies.

Purpose: This phase 1 study aims to evaluate the tolerability and the recommended phase 2 dose of selinexor in Asian patients with advanced or metastatic malignancies. Experimental Design: A total of 105 patients with advanced malignancies were enrolled from two sites in Singapore (National University Hospital and the National Cancer Centre, Singapore) from 24 February 2014 to 14 January 2019. We investigated four dosing schedules of selinexor in a 3 + 3 dose escalation design with an additional Phase 1b expansion cohort. Adverse events were graded with the NCI Common Terminology Criteria for Adverse Events v 4.03. Pharmacodynamic assessments included nuclear cytoplasmic localization of p27, XPO1 cargo proteins pre and post selinexor dosing and pharmacokinetic assessments were conducted at doses between 40 and 60 mg/m2. Results: In our Asian patient cohort, dosing at 40 mg/m2 given 2 out of 3 weeks, was the most tolerable for our patients. At this dose level, grade 3 adverse events included fatigue (8%), hyponatremia (23%), vomiting (5%), thrombocytopenia (5%), and anaemia (2%). Selinexor had a rapid oral absorption with median Tmax of 2 h and no PK accumulation after multiple doses of tested regimens. Complete responses were seen in two lymphoma patients. Partial responses were noted in three diffuse large B cell lymphomas, one Hodgkin's lymphoma and thymic carcinoma patient, respectively. Conclusion: Selinexor is tolerated by Asian patients at 40 mg/m2 twice a week given 2 out of 3 weeks. A 1-week drug holiday was needed as our patients could not tolerate the current approved continuous dosing regimens because of persistent grade 3 fatigue, anorexia and hyponatremia.

Molecular Characterization and Clinical Outcomes in RET-Rearranged NSCLC.

INTRODUCTION: RET rearrangements are an emerging targetable oncogenic fusion driver in NSCLC. However, the natural history of disease and activity of different classes of systemic therapy remain to be defined. Furthermore, molecular testing for RET is not yet routine, and the optimal method of testing is unclear. We present a comparative analysis of molecular profiling with fluorescence in situ hybridization (FISH) or next-generation sequencing (NGS) and treatment outcomes. METHODS: This study was a retrospective analysis of patients treated at the National Cancer Centre Singapore. Baseline demographics and treatment outcomes were collected. RESULTS: A total of 64 patients were included, with a median age of 62 years (range: 25-85), 56% were women, 77% were of Chinese ethnicity, 95% had adenocarcinoma, and 69% were never smokers. RET rearrangement was detected by FISH in 30 of 34 patients (88%), NGS in 40 of 43 patients (93%), and with discordant results in seven of 13 patients (54%) tested with both methods. Of 61 patients with stage IIIB/IV or recurrent disease, prevalence of central nervous system metastases was 31% and 92% received palliative systemic therapy. Overall survival was prolonged in patients treated with a selective RET tyrosine kinase inhibitor versus untreated patients (median 49.3 versus 15.3 mo; hazard ratio [HR]: 0.16, 95% confidence interval [CI]: 0.06-0.40, p < 0.001). However, it was not different in patients treated with immunotherapy versus untreated patients (median 37.7 versus 49.3 mo; HR: 1.30, 95% CI: 0.53-3.19, p = 0.53). Overall survival was also prolonged in patients with CCDC6-RET fusion versus those with KIF5B-RET fusion (median 113.5 versus 37.7 mo; HR: 0.12, 95% CI: 0.04-0.38, p = 0.009). CONCLUSIONS: In RET-rearranged NSCLC, selective RET tyrosine kinase inhibitor therapy is associated with improved survival outcomes, especially in patients with CCDC6-RET fusion. However, immunotherapy has poor efficacy. NGS and FISH testing methods may also result in substantial discordance.

Novel therapeutic avenues in triple-negative breast cancer: PI3K/AKT inhibition, androgen receptor blockade, and beyond.

Multiomic analyses have shed light upon the molecular heterogeneity and complexity of triple-negative breast cancers (TNBCs). With increasing recognition that TNBC is not a single disease entity but encompasses different disease subtypes, a one-size-fits-all treatment paradigm has become obsolete. In this context, the inhibition of phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) and androgen receptor (AR) signaling pathways have emerged as potential therapeutic strategies against selected tumors. In this paper, we reviewed the preclinical rationale, predictive biomarkers, efficacy, and safety data from early phase trials, and the future directions for these two biomarker-directed treatment approaches in TNBC.

Are There Any Clinically Relevant Subgroups of Triple-Negative Breast Cancer in 2018?

The working immunohistochemical definition of triple-negative breast cancer (TNBC) is admittedly reductionist and has only limited usefulness for informing oncologists about therapeutic decisions beyond chemotherapy. Early molecular taxonomies of TNBC based heavily on gene expression profiling, which is not readily available in the clinic today, do not necessarily encompass other molecular targets already incorporated into rationally designed clinical trials. We state that it is possible to delineate five subgroups of TNBC relevant to present-day clinical practice and cover the evidence that lends credence to emerging biomarker-directed treatment strategies for each subgroup.