The Immune-Related 27-Gene Signature DetermaIO Predicts Response to Neoadjuvant Atezolizumab plus Chemotherapy in Triple-Negative Breast Cancer.

Purpose: We assessed the 27-gene RT-qPCR-based DetermaIO assay and the same score calculated from RNA sequencing (RNA-seq) data as predictors of sensitivity to immune checkpoint therapy in the neoTRIPaPDL1 randomized trial that compared neoadjuvant carboplatin/nab-paclitaxel chemotherapy (CT) plus atezolizumab with CT alone in stage II/III triple-negative breast cancer. We also assessed the predictive function of the immuno-oncology (IO) score in expression data of patients treated with pembrolizumab plus paclitaxel (N = 29) or CT alone (N = 56) in the I-SPY2 trial.

Experimental Design: RNA-seq data were obtained from pretreatment core biopsies from 242 (93.

Spatial predictors of immunotherapy response in triple-negative breast cancer.

Immune checkpoint blockade (ICB) benefits some patients with triple-negative breast cancer, but what distinguishes responders from non-responders is unclear. Because ICB targets cell-cell interactions, we investigated the impact of multicellular spatial organization on response, and explored how ICB remodels the tumour microenvironment. We show that cell phenotype, activation state and spatial location are intimately linked, influence ICB effect and differ in sensitive versus resistant tumours early on-treatment.

A phase Ib trial of pembrolizumab plus paclitaxel or flat-dose capecitabine in 1st/2nd line metastatic triple-negative breast cancer.

Chemoimmunotherapy with anti-programmed cell death 1/ligand 1 and cytotoxic chemotherapy is a promising therapeutic modality for women with triple-negative breast cancer, but questions remain regarding optimal chemotherapy backbone and biomarkers for patient selection. We report final outcomes from a phase Ib trial evaluating pembrolizumab (200 mg IV every 3 weeks) with either weekly paclitaxel (80 mg/m weekly) or flat-dose capecitabine (2000 mg orally twice daily for 7 days of every 14-day cycle) in the 1st/2nd line setting. The primary endpoint is safety (receipt of 2 cycles without grade III/IV toxicities requiring discontinuation or ≥21-day delays).

The 27-gene IO score is associated with efficacy of PD-1/L1 inhibitors independent of FGFR expression in a real-world metastatic urothelial carcinoma cohort.

Multiple targeted therapeutics have been approved by the FDA for mUC, including immune checkpoint inhibitors (ICIs) and more recently targeted agents for both FGFR and Nectin-4. FGFR3-aberrant and Nectin-4 expressing cells have been associated with an immunosuppressed phenotype. Given that less than half of all patients respond to these agents as monotherapies and less than 20% are eligible to receive salvage therapy, effective personalized treatment plans are critical.

27-gene Immuno-Oncology (IO) Score is Associated With Efficacy of Checkpoint Immunotherapy in Advanced NSCLC: A Retrospective BC Cancer Study.

Background: Immune checkpoint inhibitors (ICI) are standard of care in advanced non-small cell lung cancer (NSCLC). However, not all patients benefit, even among PD-L1 tumor proportional score (TPS) ≥50%, indicating an unmet need for additional biomarkers such as those assessing the tumor immune microenvironment (TIME). DetermaIO is a 27-gene assay that classifies TIME and has previously demonstrated association with ICI response.

Translation of the 27-gene immuno-oncology test (IO score) to predict outcomes in immune checkpoint inhibitor treated metastatic urothelial cancer patients.

Background: The IO Score is a 27-gene immuno-oncology (IO) classifier that has previously predicted benefit to immune checkpoint inhibitor (ICI) therapy in triple negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC). It generates both a continuous score and a binary result using a defined threshold that is conserved between breast and lung. Herein, we aimed to evaluate the IO Score's binary threshold in ICI-naïve TCGA bladder cancer patients (TCGA-BLCA) and assess its clinical utility in metastatic urothelial cancer (mUC) using the IMvigor210 clinical trial treated with the ICI, atezolizumab.

Association of a novel 27-gene immuno-oncology assay with efficacy of immune checkpoint inhibitors in advanced non-small cell lung cancer.

Background: Immune checkpoint inhibitor (ICI) therapies represent a major advance in treating a variety of advanced-stage malignancies. Nevertheless, only a subset of patients benefit, even when selected based on approved biomarkers such as PD-L1 and tumor mutational burden. New biomarkers are needed to maximize the therapeutic ratio of these therapies.

Changes in Triple-Negative Breast Cancer Molecular Subtypes in Patients Without Pathologic Complete Response After Neoadjuvant Systemic Chemotherapy.

Purpose: Lehmann et al have identified four molecular subtypes of triple-negative breast cancer (TNBC)-basal-like (BL) 1, BL2, mesenchymal (M), and luminal androgen receptor-and an immunomodulatory (IM) gene expression signature modifier. Our group previously showed that the response of TNBC to neoadjuvant systemic chemotherapy (NST) differs by molecular subtype, but whether NST affects the subtype was unknown. Here, we tested the hypothesis that in patients without pathologic complete response, TNBC subtypes can change after NST.

Characterization of the tumor immune-microenvironment of adenocarcinoma of lung with a metastatic lesion in the pancreas treated successfully with first-line, single-agent pembrolizumab.

Single-agent immune checkpoint inhibitor therapy in advanced non-small cell lung cancer can significantly prolong progression-free and overall survival when compared with cytotoxic chemotherapy. Here, we report a case of newly diagnosed adenocarcinoma of the lung with a solitary brain metastasis and a biopsy confirmed adenocarcinoma in the tail of the pancreas. Cytomorphology and immunohistochemistry suggested the lung and pancreas tumors were distinct primaries.

A novel immuno-oncology algorithm measuring tumor microenvironment to predict response to immunotherapies.

Immune checkpoint inhibitor (ICI) therapies can improve clinical outcomes for patients with solid tumors, but relatively few patients respond. Because ICI therapies support an adaptive immune response, patients with an active tumor microenvironment (TME) may be more likely to respond, and thus biomarkers capable of discerning an active from a quiescent TME may be useful in patient selection. We developed an algorithm optimized for genes expressed in the mesenchymal and immunomodulatory subtypes of a 101-gene triple negative breast cancer model (Ring, BMC Cancer, 2016, 16:143) as a means to capture the immunological state of the TME.

Rates of immune cell infiltration in patients with triple-negative breast cancer by molecular subtype.

In patients with triple-negative breast cancer (TNBC), tumor-infiltrating lymphocytes (TILs) are associated with improved survival. Lehmann et al. identified 4 molecular subtypes of TNBC [basal-like (BL) 1, BL2, mesenchymal (M), and luminal androgen receptor (LAR)], and an immunomodulatory (IM) gene expression signature indicates the presence of TILs and modifies these subtypes.

Comparison of triple-negative breast cancer molecular subtyping using RNA from matched fresh-frozen versus formalin-fixed paraffin-embedded tissue.

Background: Triple negative breast cancer (TNBC) is a heterogeneous disease that lacks unifying molecular alterations that can guide therapy decisions. We previously identified distinct molecular subtypes of TNBC (TNBCtype) using gene expression data generated on a microarray platform using frozen tumor specimens. Tumors and cell lines representing the identified subtypes have distinct enrichment in biologically relevant transcripts with differing sensitivity to standard chemotherapies and targeted agents.

Generation of an algorithm based on minimal gene sets to clinically subtype triple negative breast cancer patients.

Background: Recently, a gene expression algorithm, TNBCtype, was developed that can divide triple-negative breast cancer (TNBC) into molecularly-defined subtypes. The algorithm has potential to provide predictive value for TNBC subtype-specific response to various treatments. TNBCtype used in a retrospective analysis of neoadjuvant clinical trial data of TNBC patients demonstrated that TNBC subtype and pathological complete response to neoadjuvant chemotherapy were significantly associated.

Expression of a-Tocopherol-Associated protein (TAP) is associated with clinical outcome in breast cancer patients.

Background: The role of vitamin E in breast cancer prevention and treatment has been widely investigated, and the different tocopherols that comprise this nutrient have been shown to have divergent associations with cancer outcome. Our previous studies have shown that α-Tocopherol-associated protein (TAP), a vitamin E binding protein, may function as a tumor suppressor-like factor in breast carcinogenesis. The current study addresses the association of TAP expression with breast cancer clinical outcomes.

Mammostrat as an immunohistochemical multigene assay for prediction of early relapse risk in the tamoxifen versus exemestane adjuvant multicenter trial pathology study.

Purpose: Some postmenopausal patients with hormone-sensitive early breast cancer remain at high risk of relapse despite endocrine therapy and, in addition, might benefit from adjuvant chemotherapy. The challenge is to prospectively identify such patients. The Mammostrat test uses five immunohistochemical markers to stratify patients regarding recurrence risk and may inform treatment decisions.

TLE3 expression is associated with sensitivity to taxane treatment in ovarian carcinoma.

Background: We have previously shown that transducin-like enhancer of split 3 (TLE3) is associated with outcome specifically in patients with taxane-treated breast cancer and not in patients treated with anthracycline-based regimens without a taxane. The purpose of this study was to assess the association between TLE3 expression and recurrence in patients with ovarian carcinoma treated with a taxane containing regimen as opposed to those treated with a platinum-based agent alone.

Methods: We carried out immunohistochemical staining of TLE3 in two series of ovarian cancer specimens from the University of Alabama at Birmingham, Birmingham, AL and the Royal Hospital for Women, Sydney, Australia.

Angiosarcoma: a study of 98 cases with immunohistochemical evaluation of TLE3, a recently described marker of potential taxane responsiveness.

Angiosarcomas may be primary in the skin, primary in soft tissue or viscera, or secondary to irradiation. All angiosarcomas have a poor prognosis. Taxanes may have efficacy in the treatment of angiosarcoma.

Mammostrat as a tool to stratify breast cancer patients at risk of recurrence during endocrine therapy.

Introduction: Patients with early-stage breast cancer, treated with endocrine therapy, have approximately 90% 5-year disease-free survival. However, for patients at higher risk of relapse despite endocrine therapy, additional adjuvant therapy, such as chemotherapy, may be indicated. The challenge is to prospectively identify such patients.

The expression of TRMT2A, a novel cell cycle regulated protein, identifies a subset of breast cancer patients with HER2 over-expression that are at an increased risk of recurrence.

Background: Over-expression of HER2 in a subset of breast cancers (HER2+) is associated with high histological grade and aggressive clinical course. Despite these distinctive features, the differences in response of HER2+ patients to both adjuvant cytotoxic chemotherapy and targeted therapy (e.g.

A novel five-antibody immunohistochemical test for subclassification of lung carcinoma.

Malignant epithelial lung carcinoma can be subclassified by histology into several tumor types, including adenocarcinoma and squamous cell carcinoma. The need for a uniform method of classifying lung carcinomas is growing as clinical trials reveal treatment and side effect differences associated with histological subtypes. Diagnosis is primarily performed by morphological assessment.

TLE3 as a candidate biomarker of response to taxane therapy.

Introduction: The addition of taxanes (Ts) to chemotherapeutic regimens has not demonstrated a consistent benefit in early-stage breast cancer. To date, no clinically relevant biomarkers that predict T response have been identified.

Methods: A dataset of immunohistochemistry stains in 411 patients was mined to identify potential markers of response.

Chemosensitivity and stratification by a five monoclonal antibody immunohistochemistry test in the NSABP B14 and B20 trials.

Purpose: To test the association between risk stratification and outcome in a prospectively designed, blinded retrospective study using tissue arrays of available paraffin blocks from the estrogen receptor-expressing, node-negative samples from the National Surgical Adjuvant Breast and Bowel Project B14 and B20 tamoxifen and chemotherapy trials.

Experimental Design: Tissue arrays were stained by immunohistochemistry targeting p53, NDRG1, SLC7A5, CEACAM5, and HTF9C. Risk stratification was done using predefined scoring rules, algorithm for combining scores, and cutoff points for low-risk, moderate-risk, and high-risk patient strata.

Lipoxygenase pathway receptor expression in ovarian cancer.

Objective: To determine the expression of lipoxygenase (LOX) pathway receptors in ovarian cancer as a potential target for anti-LOX-based therapy.

Study Design: Paraffin-embedded tumor samples from epithelial ovarian cancer patients were used to construct tissue microarrays to stain for the proposed sites of inhibition of a LOX inhibitor (5-LOX, LTB4-BLT1, and LTB4-BLT2).

Results: 245 samples were available for interpretation.

Tools to study the function of the Ras-related, estrogen-regulated growth inhibitor in breast cancer.

The Ras-related, estrogen-regulated growth inhibitor (Rerg) is a Ras-related small GTPase and candidate tumor suppressor. Rerg gene expression is stimulated by the estrogen receptor alpha (ERalpha), and Rerg gene expression is absent in ER-negative breast cancers. ER-negative breast cancers are highly invasive and metastastic and are typically more advanced than their ER-positive counterparts.