Discordance between oncotype DX recurrence score and RSPC for predicting residual risk of recurrence in ER-positive breast cancer.

PURPOSE: Oncotype DX, a gene expression assay widely employed to aid decision making on adjuvant chemotherapy use in patients with primary oestrogen receptor-positive (ER+) breast cancer, produces a recurrence score (RS) related to distant disease recurrence (DR) risk (RS%). In node-negative patients, RS can be integrated with clinicopathological parameters to derive RS-pathology-clinical (RSPC) that improves prognostic accuracy. METHODS: Data were collected on patients having clinically indicated tests with an intermediate clinical risk of distant recurrence, and for whom the decision to prescribe chemotherapy remained unclear. Correlation between RS% and RSPC scores was examined. An agreement table was constructed using risk-categorised data. Association between RS%-derived categorical risk assignments and treatment recommendation was evaluated. RESULTS: Data on 171 tests (168 patients) were available. Median DR risk by RS% was 11% (range 3-34%), by RSPC it was 15% (range 4-63%). Correlation between RS% and RSPC was 0.702 (p < 0.001). RS% classified 57.3% of cases as low-, 32.2% intermediate- and 10.5% high-risk for DR; by RSPC proportions were 33.9, 35.7, and 30.4%, respectively. The number of patients receiving chemotherapy recommendations was: 14/87 (16.1%) categorised as low-risk by RS%, 27/49 (55.1%) as intermediate-risk and 12/13 (92.3%) as high-risk. Of 149 patients recommended for endocrine treatment alone, 28 (18.8%) were categorised by RS% as low-risk but by RSPC as intermediate- or high-risk. CONCLUSIONS: In this group of patients, RSPC assessed fewer patients as low-risk and more as high-risk than did RS%. The discordances between the scores indicate that RSPC estimates of risk should be considered when selecting patients for endocrine therapy alone.

Stratification of PD-1 blockade response in melanoma using pre- and post-treatment immunophenotyping of peripheral blood.

Efficacy of checkpoint inhibitor therapies in cancer varies greatly, with some patients showing complete responses while others do not respond and experience progressive disease. We aimed to identify correlates of response and progression following PD-1-directed therapy by immunophenotyping peripheral blood samples from 20 patients with advanced malignant melanoma before and after treatment with the PD-1 blocking antibody pembrolizumab. Our data reveal that individuals responding to PD-1 blockade were characterised by increased CD8 T cell proliferation following treatment, while progression was associated with an increase in CTLA-4-expressing Treg. Remarkably, unsupervised clustering analysis of pre-treatment T cell subsets revealed differences in individuals that went on to respond to PD-1 blockade compared to individuals that did not. These differences mapped to expression of the proliferation marker Ki67 and the costimulatory receptor CD28 as well as the inhibitory molecules 2B4 and KLRG1. While these results require validation in larger patient cohorts, they suggest that flow cytometric analysis of a relatively small number of T cell markers in peripheral blood could potentially allow stratification of PD-1 blockade treatment response prior to therapy initiation.

The successful use of pembrolizumab in a renal transplant recipient with metastatic melanoma.

We report a case in which a renal transplant recipient with metastatic melanoma had an excellent response to treatment with second line programmed cell death protein 1 (PD-1) inhibitor therapy, pembrolizumab. Acute cellular allograft rejection on initiation of PD-1 inhibitor was successfully reversed with methylprednisolone. By converting the patient to sirolimus and giving predose prednisolone, pembrolizumab was continued with stable renal function and an excellent oncological response. This case supports the efficacy of PD-1 inhibitors in patients who are chronically immunosuppressed, and suggests an approach to maintain transplant function.

Histology-Driven Therapy: The Importance of Diagnostic Accuracy in Guiding Systemic Therapy of Soft Tissue Tumors.

Soft tissue tumors (STTs) are rare mesenchymal neoplasms accounting for less than 1% of adult cancers. More than 50 different subtypes of STTs have been identified, with this number expected to grow as our understanding of the complex genetic landscape of these diseases improves. As the classification of soft tissue neoplasms continues to diversify, so does the approach to therapy. Accurate histopathologic diagnosis, utilizing the appropriate ancillary immunohistochemical and molecular diagnostic platforms, underpins the oncologic management of soft tissue sarcomas. As increasing numbers of reproducible genetic abnormalities in soft tissue neoplasms are defined, molecular genetic and molecular cytogenetic investigations have become a standard part of the ancillary diagnostic repertoire. However, other soft tissue neoplasms lack reproducible genetic abnormalities, and for these, traditional histology and immunohistochemistry remain the cornerstones for diagnosis. Here, we give an overview of histology-driven therapy in STTs, highlighting the critical role of accurate surgical pathology in guiding the systemic treatment of patients with these neoplasms, and the importance of close collaboration between the surgical pathologist and the oncologist. We also summarize what is considered standard practice in nonhistology- and histology-driven therapy.

Changes in Expression of Genes Representing Key Biologic Processes after Neoadjuvant Chemotherapy in Breast Cancer, and Prognostic Implications in Residual Disease.

PURPOSE: The primary aim was to derive evidence for or against the clinical importance of several biologic processes in patients treated with neoadjuvant chemotherapy (NAC) by assessing expression of selected genes with prior implications in prognosis or treatment resistance. The secondary aim was to determine the prognostic impact in residual disease of the genes' expression. EXPERIMENTAL DESIGN: Expression levels of 24 genes were quantified by NanoString nCounter on formalin-fixed paraffin-embedded residual tumors from 126 patients treated with NAC and 56 paired presurgical biopsies. The paired t test was used for testing changes in gene expression, and Cox regression and penalized elastic-net Cox Regression for estimating HRs. RESULTS: After NAC, 12 genes were significantly up- and 8 downregulated. Fourteen genes were significantly associated with time to recurrence in univariable analysis in residual disease. In a multivariable model, ACACB, CD3D, MKI67, and TOP2A added prognostic value independent of clinical ER(-), PgR(-), and HER2(-) status. In ER(+)/HER2(-) patients, ACACB, PAWR, and ERBB2 predicted outcome, whereas CD3D and PAWR were prognostic in ER(-)/HER2(-) patients. By use of elastic-net analysis, a 6-gene signature (ACACB, CD3D, DECORIN, ESR1, MKI67, PLAU) was identified adding prognostic value independent of ER, PgR, and HER2. CONCLUSIONS: Most of the tested genes were significantly enriched or depleted in response to NAC. Expression levels of genes representing proliferation, stromal activation, metabolism, apoptosis, stemcellness, immunologic response, and Ras-ERK activation predicted outcome in residual disease. The multivariable gene models identified could, if validated, be used to identify patients needing additional post-neoadjuvant treatment to improve prognosis. Clin Cancer Res; 22(10); 2405-16. ©2016 AACR.

The effect of training distinct neurofeedback protocols on aspects of cognitive performance.

The use of neurofeedback as an operant conditioning paradigm has disclosed that participants are able to gain some control over particular aspects of their electroencephalogram (EEG). Based on the association between theta activity (4-7 Hz) and working memory performance, and sensorimotor rhythm (SMR) activity (12-15 Hz) and attentional processing, we investigated the possibility that training healthy individuals to enhance either of these frequencies would specifically influence a particular aspect of cognitive performance, relative to a non-neurofeedback control-group. The results revealed that after eight sessions of neurofeedback the SMR-group were able to selectively enhance their SMR activity, as indexed by increased SMR/theta and SMR/beta ratios. In contrast, those trained to selectively enhance theta activity failed to exhibit any changes in their EEG. Furthermore, the SMR-group exhibited a significant and clear improvement in cued recall performance, using a semantic working memory task, and to a lesser extent showed improved accuracy of focused attentional processing using a 2-sequence continuous performance task. This suggests that normal healthy individuals can learn to increase a specific component of their EEG activity, and that such enhanced activity may facilitate semantic processing in a working memory task and to a lesser extent focused attention. We discuss possible mechanisms that could mediate such effects and indicate a number of directions for future research.

Predicting response to cytotoxic drugs--the endocrine part of the story.

The substantial reduction in risk of recurrence and mortality in premenopausal breast cancer patients of estrogen deprivation as treatment for early ER+ breast cancer is well accepted. Surgical, radiotherapeutic or medical approaches to ovarian ablation/suppression all seem to be similarly effective and appear to be at least partially additive to the reduction seen with chemotherapy. Cytotoxic treatment of premenopausal women also frequently elicits a reduction in frequency and regularity of menstruation and sometimes a complete and permanent amenorrhea as a reflection of reduced ovarian activity. While it is certain that the associated reduction in estrogenic exposure of patients contributes to the overall effectiveness of chemotherapy in some premenopausal women the degree to which this is the case is a subject of vigorous debate. Furthermore, the extent to which chemotherapy induced ovarian suppression impacts on molecular predictors of chemotherapy benefit is poorly understood and recommendations for further study of this issue are made.

Targeting endocrine resistance: is there a role for mTOR inhibition?

The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is a critical intracellular signaling cascade that mediates both growth factor-induced proliferation and cell survival with deregulated signaling through this pathway, a feature of most cancers. Here, we review the role of the PI3K/Akt/mTOR pathway in endocrine-resistant breast cancer and discuss preclinical and clinical studies combining endocrine therapy with mTOR inhibition. Key to the success of such an approach will be a clinical trial design incorporating appropriate tumor selection and validation of biomarkers predicting benefit. Ultimately, a greater understanding of the biology and compensatory mechanisms will allow the partnering of key signal transduction inhibitors together to provide maximal "vertical" or "horizontal" blockade with further preclinical and clinical studies planned to examine possible synergistic combinations with endocrine therapy.