Immunologic Factors Associated with Differential Response to Neoadjuvant Chemoimmunotherapy in Triple-Negative Breast Cancer.

Background: KEYNOTE-522 resulted in FDA approval of the immune checkpoint inhibitor pembrolizumab in combination with neoadjuvant chemotherapy for patients with early-stage, high-risk, triple-negative breast cancer (TNBC). Unfortunately, pembrolizumab is associated with several immune-related adverse events (irAEs). We aimed to identify potential tumor microenvironment (TME) biomarkers which could predict patients who may attain pathological complete response (pCR) with chemotherapy alone and be spared the use of anti-PD-1 immunotherapy. Methods: Comprehensive immune profiling, including RNA-seq gene expression assessment of 395 immune genes, was performed on matched FFPE tumor samples from 22 stage I-III TNBC patients (14 patients treated with neoadjuvant chemotherapy alone (NAC) and 8 treated with neoadjuvant chemotherapy combined with pembrolizumab (NAC+I)). Results: Differential gene expression analysis revealed that in the NAC group, IL12B and IL13 were both significantly associated with pCR. In the NAC+I group, LCK and TP63 were significantly associated with pCR. Patients in both treatment groups exhibiting pCR tended to have greater tumor inflammation than non-pCR patients. In the NAC+I group, patients with pCR tended to have greater cell proliferation and higher PD-L1 expression, while in the NAC group, patients with pCR tended to have lower cancer testis antigen expression. Additionally, the NAC+I group trended toward a lower relative dose intensity averaged across all chemotherapy drugs, suggesting that more dose reductions or treatment delays occurred in the NAC+I group than the NAC group. Conclusions: A comprehensive understanding of immunologic factors could potentially predict pCR to chemotherapy alone, enabling the avoidance of the unnecessary treatment of these patients with checkpoint inhibitors.

Transcriptomic analysis of GITR and GITR ligand reveals cancer immune heterogeneity with implications for GITR targeting.

Glucocorticoid-induced tumor necrosis factor related protein (GITR) is a transmembrane protein expressed mostly on CD25+CD4+ regulatory T-cells (Tregs) and upregulated on all T-cells upon activation. It is a T-cell co-stimulatory receptor and has demonstrated promising anti-tumor activity in pre-clinical studies. To date, however, the efficacy of GITR agonism has been discouraging in clinical trials. This study explores GITR and GITR ligand (GITR-L) ribonucleic acid (RNA) expression in solid tumors in an attempt to delineate causes for variable responses to GITR agonists. RNA expression levels of 514 patients with a variety of cancer types were normalized to internal housekeeping gene profiles and ranked as percentiles. 99/514 patients (19.3%) had high GITR expression (defined as ≥ 75th percentile). Breast and lung cancer had the highest proportion of patients with high GITR expression (39% and 35%, respectively). The expression of concomitant high GITR and low-moderate GITR-L expression (defined as <75th percentile) was present in 31% and 30% of patients with breast and lung cancer respectively. High GITR expression also showed a significant independent association with high RNA expression of other immune modulator proteins, namely, PD-L1 immunohistochemistry (IHC) ≥1 (odds ratio (OR) 2.15, P=0.008), CTLA4 (OR=2.17, P=0.05) and OX40 high RNA expression (OR=2.64, P=0.001). Overall, these results suggest that breast and lung cancer have a high proportion of patients with a GITR and GITR-L RNA expression profile that merits further investigation in GITR agonism studies. The association of high GITR expression with high CTLA4 and OX40 RNA expression, as well as positive PD-L1 IHC, provides a rationale for a combination approach targeting these specific immune modulator proteins in patients whose tumors show such co-expression.

The Impact of Prior Single-Gene Testing on Comprehensive Genomic Profiling Results for Patients with Non-Small Cell Lung Cancer.

INTRODUCTION: Tissue-based broad molecular profiling of guideline-recommended biomarkers is advised for the therapeutic management of patients with non-small cell lung cancer (NSCLC). However, practice variation can affect whether all indicated biomarkers are tested. We aimed to evaluate the impact of common single-gene testing (SGT) on subsequent comprehensive genomic profiling (CGP) test outcomes and results in NSCLC. METHODS: Oncologists who ordered SGT for guideline-recommended biomarkers in NSCLC patients were prospectively contacted (May-December 2022) and offered CGP (DNA and RNA sequencing), either following receipt of negative SGT findings, or instead of SGT for each patient. We describe SGT patterns and compare CGP completion rates, turnaround time, and recommended biomarker detection for NSCLC patients with and without prior negative SGT results. RESULTS: Oncologists in > 80 community practices ordered CGP for 561 NSCLC patients; 135 patients (27%) first had negative results from 30 different SGT combinations; 84% included ALK, EGFR and PD-L1, while only 3% of orders included all available SGTs for guideline-recommended genes. Among patients with negative SGT results, CGP was attempted using the same tissue specimen 90% of the time. There were also significantly more CGP order cancellations due to tissue insufficiency (17% vs. 7%), DNA sequencing failures (13% vs. 8%), and turnaround time > 14 days (62% vs. 29%) than among patients who only had CGP. Forty-six percent of patients with negative prior SGT had positive CGP results for recommended biomarkers, including targetable genomic variants in genes beyond ALK and EGFR, such as ERBB2, KRAS (non-G12C), MET (exon 14 skipping), NTRK2/3, and RET . CONCLUSION: For patients with NSCLC, initial use of SGT increases subsequent CGP test cancellations, turnaround time, and the likelihood of incomplete molecular profiling for guideline-recommended biomarkers due to tissue insufficiency.

Patients with non-small cell lung cancer (NSCLC) should have their tumor tissue tested for all recommended biomarkers that can help identify their best treatment options. Traditional tests look at gene biomarkers one by one (single-gene testing), and doctors can order some or all these tests individually or in a group. However, some recommended biomarkers cannot be tested by traditional single-gene tests at all. Newer technology (next-generation sequencing) covers all current recommended treatment biomarkers in one test (comprehensive genomic profiling), but this testing is more expensive and can take more time. Our study shows that NSCLC patients do not get all recommended treatment biomarkers tested when a single-gene testing approach is taken. Single-gene testing also used up some patients' tumor tissue entirely, such that further testing by comprehensive genomic profiling could not be done at all (17% vs. 7% for patients with no prior single-gene tests), resulted in more sequencing failures (13% vs. 8%), and had turnaround time for results greater than 14 days for more patients (62% vs. 29%). When comprehensive genomic profiling was completed, 46% of patients with negative results from prior single-gene testing had positive results for recommended treatment biomarkers that were not included in the initial single-gene tests. To ensure that NSCLC patients receive testing for all recommended biomarkers, comprehensive genomic profiling must be performed first.

Cancer testis antigen burden (CTAB): a novel biomarker of tumor-associated antigens in lung cancer.

BACKGROUND: Cancer-testis antigens (CTAs) are tumor antigens that are normally expressed in the testes but are aberrantly expressed in several cancers. CTA overexpression drives the metastasis and progression of lung cancer, and is associated with poor prognosis. To improve lung cancer diagnosis, prognostic prediction, and drug discovery, robust CTA identification and quantitation is needed. In this study, we examined and quantified the co-expression of CTAs in lung cancer to derive cancer testis antigen burden (CTAB), a novel biomarker of immunotherapy response. METHODS: Formalin fixed paraffin embedded (FFPE) tumor samples in discovery cohort (n = 5250) and immunotherapy and combination therapy treated non-small cell lung cancer (NSCLC) retrospective (n = 250) cohorts were tested by comprehensive genomic and immune profiling (CGIP), including tumor mutational burden (TMB) and the mRNA expression of 17 CTAs. PD-L1 expression was evaluated by IHC. CTA expression was summed to derive the CTAB score. The median CTAB score for the discovery cohort of 170 was applied to the retrospective cohort as cutoff for CTAB "high" and "low". Biomarker and gene expression correlation was measured by Spearman correlation. Kaplan-Meier survival analyses were used to detect overall survival (OS) differences, and objective response rate (ORR) based on RECIST criteria was compared using Fisher's exact test. RESULTS: The CTAs were highly co-expressed (p < 0.05) in the discovery cohort. There was no correlation between CTAB and PD-L1 expression (R = 0.011, p = 0.45) but some correlation with TMB (R = 0.11, p = 9.2 × 10-14). Kaplan-Meier survival analysis of the immunotherapy-treated NSCLC cohort revealed better OS for the pembrolizumab monotherapy treated patients with high CTAB (p = 0.027). The combination group demonstrated improved OS compared to pembrolizumab monotherapy group (p = 0.04). The pembrolizumab monotherapy patients with high CTAB had a greater ORR than the combination therapy group (p = 0.02). CONCLUSIONS: CTA co-expression can be reliably measured using CGIP in solid tumors. As a biomarker, CTAB appears to be independent from PD-L1 expression, suggesting that CTAB represents aspects of tumor immunogenicity not measured by current standard of care testing. Improved OS and ORR for high CTAB NSCLC patients treated with pembrolizumab monotherapy suggests a unique underlying aspect of immune response to these tumor antigens that needs further investigation.

Clinical Utility of 18F-FDG PET/CT in Staging Localized Breast Cancer Before Initiating Preoperative Systemic Therapy.

BACKGROUND: 18F-fluorodeoxyglucose PET/CT is recommended as an optional study in the current NCCN Clinical Practice Guidelines in Oncology for Breast Cancer after CT of the chest, abdomen, and pelvis with contrast and bone scan (CTBS) in stage IIA-IIIC breast cancer. We evaluated our experience with the use of PET/CT in this setting before beginning primary systemic therapy (PST) prior to planned surgery. METHODS: We performed medical record abstractions of all adult female patients with clinical stage IIA-IIIC breast cancer diagnosed at Montefiore Medical Center from January 1, 2014, through January 1, 2019, who underwent PET/CT before PST. We calculated the proportion of patients upstaged after PET/CT and examined the cost and radiation exposure associated with PET/CT compared with CTBS. RESULTS: A total of 195 patients with 196 breast cancers (bilateral disease in 1 patient) met the study inclusion criteria and had PET/CT as the first imaging study before PST. The overall upstaging rate for regional nodal metastasis and/or distant metastasis was 37% (73/196), including 24% for stage IIA (9/38), 39% for stage IIB (31/79), 54% for stage IIIA (22/41), 27% for stage IIIB (8/30), and 37% for stage IIIC (3/8). The overall upstaging rate for distant metastasis was 14% (27/196), including 0% for stage IIA, 13% for stage IIB (10/79), 22% for stage IIIA (9/41), 17% for stage IIIB (5/30), and 37% for stage IIIC (3/8). Medicare reimbursement rates were $1,604.37 for PET/CT and $1,679.94 for CTBS. The radiation dose for PET/CT was 14 mSv versus 21 mSv for CTBS. CONCLUSIONS: Approximately 37% of patients with clinical stage IIA-IIIC breast cancer who underwent PET/CT before PST showed more extensive disease, including 23% with more extensive nodal metastasis and 14% with distant metastasis. Given its high detection rate, comparable cost, lower radiation dose, and greater convenience, PET/CT should be considered as an alternative to CTBS rather than "optional" after CTBS, especially in patients who require an efficient and expeditious workup before initiating PST.

Predictors of Survival in Patients with Advanced Gastrointestinal Malignancies Admitted to the Intensive Care Unit.

BACKGROUND: Patients with cancer have a high use of health care utilization at the end of life, which can frequently involve admissions to the intensive care unit (ICU). We sought to evaluate the predictors for outcome in patients with gastrointestinal (GI) cancer admitted to the ICU for nonsurgical conditions. PATIENTS AND METHODS: The primary objective was to determine the predictors of hospital mortality. Secondary objectives included investigating the predictors of ICU mortality and hospital overall survival (OS). All patients with GI cancer admitted to the ICU at the University of Texas MD Anderson Cancer Center between November 2012 and February 2015 were retrospectively analyzed. Cancer characteristics, treatment characteristics, and Sequential Organ Failure Assessment (SOFA) scores were analyzed for their effects on survival. RESULTS: The characteristics of the 200 patients were as follows: 64.5% male, mean age of 60 years, median SOFA score of 6.7, and tumor types of intestinal (37.5%), hepatobiliary/pancreatic (36%), and gastroesophageal (24%). The hospital mortality was 41%, and overall 6-month mortality was 75%. In multivariate analysis, high admission SOFA score > 5, poor tumor differentiation, and duration of metastatic disease ≤7 months were associated with increased hospital mortality. For OS, high admission SOFA score > 5, poor tumor differentiation, and patients who were not on active chemotherapy because of poor performance had worse outcome. In multivariate analysis, SOFA score remained significant for OS even after excluding patients who died in the ICU. CONCLUSION: For patients with metastatic GI cancer admitted to the ICU, SOFA score was predictive for both acute and long-term survival. A patient's chemotherapy treatment status was not predictive for hospital mortality but was for OS. The SOFA score should be utilized in all patients with GI cancer upon ICU admission for prognostication. IMPLICATIONS FOR PRACTICE: Patients with cancer have a high use of health care utilization at the end of life, which can frequently involve admissions to the intensive care unit (ICU). Although there have been substantial increases in duration of survival for patients with advanced metastatic cancer, their mortality after an ICU admission remains high. GI malignancy is considered one of the top three lethal cancers estimated in 2017. Survival of critically ill patients with advanced GI cancer should be evaluated to help guide treatment planning.

Poor outcomes associated with +der(22)t(9;22) and -9/9p in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia receiving chemotherapy plus a tyrosine kinase inhibitor.

In patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) treated with chemotherapy plus a tyrosine kinase inhibitor (TKI), the prognostic impact of additional chromosomal abnormalities (ACAs) is not well-established. We evaluated the prognostic impact of individual ACAs in 152 patients with Ph+ ALL receiving first-line intensive chemotherapy plus either imatinib (n = 36), dasatinib (n = 74), or ponatinib (n = 42). ACAs were identified in 118 patients (78%). Compared to outcomes of patients without ACAs, ACAs were not associated with differences in either relapse-free survival (RFS; P = 0.42) or overall survival (OS; P = 0.51). When individual ACAs were evaluated, +der(22)t(9;22) and/or -9/9p in the absence of high hyperdiploidy (HeH) was present in 16% of patients and constituted a poor-risk ACA group. Patients with one or more poor-risk ACAs in the absence of HeH had significantly shorter RFS (5-year RFS rate 33% versus 59%, P = 0.01) and OS (5-year OS rate 24% versus 63%, P = 0.003). Poor-risk ACAs were prognostic in patients who received imatinib and dasatinib but not in those who received ponatinib. By multivariate analysis, this poor-risk ACA group was independently associated with worse RFS (HR 2.03 [95% CI 1.08-3.30], P = 0.03) and OS (HR 2.02 [95% CI 1.10-3.71], P = 0.02). Patients with Ph+ ALL who have +der(22)t(9;22) and/or -9/9p in the absence of HeH have relatively poor outcomes when treated with chemotherapy plus a TKI.

Hemolytic uremic syndrome associated with Escherichia coli O157:H7 infection in older adults: a case report and review of the literature.

BACKGROUND: Hemolytic uremic syndrome associated with Shiga toxin-producing Escherichia coli O157:H7 has been widely known as a common cause of acute renal failure in children. There are only a few reports of sporadic Shiga toxin-producing Escherichia coli-hemolytic uremic syndrome in adults in the USA. Analyses from the 2011 outbreak of hemolytic uremic syndrome associated with Escherichia coli O104:H4 reported that mortality rates are highest in those patients with age >60-years old. Therefore, recognizing Shiga toxin-producing Escherichia coli-hemolytic uremic syndrome in older people can help early introduction of the appropriate therapy. CASE PRESENTATION: We describe an 86-year-old Caucasian woman, initially treated as suspected thrombotic thrombocytopenic purpura, with worsening neurological and renal functions despite plasmapheresis (plasma exchange). A subsequent normal ADAMTS13 activity level and positive stool sample for Escherichia coli O157:H7 confirmed the diagnosis of Shiga toxin-associated hemolytic uremic syndrome. We shifted our management towards aggressive supportive care. Despite conventional treatment, hemolytic uremic syndrome unfortunately led to her death. CONCLUSIONS: Our case demonstrates the importance of recognizing Shiga toxin-producing Escherichia coli-hemolytic uremic syndrome as an etiology of microangiopathic hemolytic anemia in older people. According to the current literature, supportive care is the best approach for Shiga toxin-producing Escherichia coli-hemolytic uremic syndrome. Therapies such as plasma exchange and eculizumab (a complement inhibitor) are not shown to be effective in Shiga toxin-producing Escherichia coli-hemolytic uremic syndrome. There is a dire need to continue research to find better treatment options in this disease entity with a high mortality, particularly in older people.