Jimmy Ruiz

Interactions between immunity, proliferation and molecular subtype in breast cancer prognosis

BackgroundGene expression signatures indicative of tumor proliferative capacity and tumor-immune cell interactions have emerged as principal biology-driven predictors of breast cancer outcomes. How these signatures relate to one another in biological and prognostic contexts remains to be clarified.ResultsTo investigate the relationship between proliferation and immune gene signatures, we analyzed an integrated dataset of 1,954 clinically annotated breast tumor expression profiles randomized into training and test sets to allow two-way discovery and validation of gene-survival associations. Hierarchical clustering revealed a large cluster of distant metastasis-free survival-associated genes with known immunological functions that further partitioned into three distinct immune metagenes likely reflecting B cells and/or plasma cells; T cells and natural killer cells; and monocytes and/or dendritic cells. A proliferation metagene allowed stratification of cases into proliferation tertiles. The prognostic strength of these metagenes was largely restricted to tumors within the highest proliferation tertile, though intrinsic subtype-specific differences were observed in the intermediate and low proliferation tertiles. In highly proliferative tumors, high tertile immune metagene expression equated with markedly reduced risk of metastasis whereas tumors with low tertile expression of any one of the three immune metagenes were associated with poor outcome despite higher expression of the other two metagenes.ConclusionsThese findings suggest that a productive interplay among multiple immune cell types at the tumor site promotes long-term anti-metastatic immunity in a proliferation-dependent manner. The emergence of a subset of effective immune responders among highly proliferative tumors has novel prognostic ramifications.

Low-grade gliomas.

Opinion statementLow-grade gliomas (LGG) are uncommon central nervous system (CNS) tumors which often present with seizures and few other neurologic signs or symptoms. Multimodality therapy encompassing surgical resection, radiation therapy (RT), and chemotherapy may provide the best disease-free and overall survival (OS). Each of these treatment modalities plays an important role in the treatment of these tumors. The understanding and management of LGG is evolving as randomized clinical trials have begun to address many questions related to the timing and order of each of the available treatments and their individual and combined effects on progression-free survival (PFS) and OS. Currently, an attempt at surgical resection followed by external beam RT is a typical treatment approach, at least in high-risk patients. Observation with serial brain imaging studies or surgical resection or debulking alone may be acceptable options in patients with low-risk tumors. The role of chemotherapy in either group is less clear, but recent studies have indicated that concurrent chemotherapy with radiation improves PFS and may eventually impact OS. The European Organization for Research and Treatment of Cancer (EORTC) and the Radiation Therapy Oncology Group (RTOG) are currently conducting two large Phase III and Phase II studies, respectively. The studies seek to evaluate the efficacy of radiotherapy and either temozolomide or a combination of procarbazine, vincristine, and lomustine in high-risk LGG patients. Ongoing investigative efforts seek to confirm the predictive value of a number of molecular markers including the loss of chromosomes 1p and 19q and the epigenetic silencing of the methylguanine-DNA methyltransferase (MGMT) gene. Additional smaller clinical trials seek to establish the role of newer targeted therapies including small-molecule tyrosine kinase inhibitors in patients with newly diagnosed and recurrent LGG.

Predictors of neurologic and nonneurologic death in patients with brain metastasis initially treated with upfront stereotactic radiosurgery without whole-brain radiation therapy

Background In this study we attempted to discern the factors predictive of neurologic death in patients with brain metastasis treated with upfront stereotactic radiosurgery (SRS) without whole brain radiation therapy (WBRT) while accounting for the competing risk of nonneurologic death. Methods We performed a retrospective single-institution analysis of patients with brain metastasis treated with upfront SRS without WBRT. Competing risks analysis was performed to estimate the subdistribution hazard ratios (HRs) for neurologic and nonneurologic death for predictor variables of interest. Results Of 738 patients treated with upfront SRS alone, neurologic death occurred in 226 (30.6%), while nonneurologic death occurred in 309 (41.9%). Multivariate competing risks analysis identified an increased hazard of neurologic death associated with diagnosis-specific graded prognostic assessment (DS-GPA) ≤ 2 (P = .005), melanoma histology (P = .009), and increased number of brain metastases (P<.001), while there was a decreased hazard associated with higher SRS dose (P = .004). Targeted agents were associated with a decreased HR of neurologic death in the first 1.5 years (P = .04) but not afterwards. An increased hazard of nonneurologic death was seen with increasing age (P =.03), nonmelanoma histology (P<.001), presence of extracranial disease (P<.001), and progressive systemic disease (P =.004). Conclusions Melanoma, DS-GPA, number of brain metastases, and SRS dose are predictive of neurologic death, while age, nonmelanoma histology, and more advanced systemic disease are predictive of nonneurologic death. Targeted agents appear to delay neurologic death.

Repeat stereotactic radiosurgery as salvage therapy for locally recurrent brain metastases previously treated with radiosurgery

OBJECTIVE There are a variety of salvage options available for patients with brain metastases who experience local failure after stereotactic radiosurgery (SRS). These options include resection, whole-brain radiation therapy, laser thermoablation, and repeat SRS. There is little data on the safety and efficacy of repeat SRS following local failure of a prior radiosurgical procedure. This study evaluates the clinical outcomes and dosimetric characteristics of patients who experienced tumor recurrence and were subsequently treated with repeat SRS. METHODS Between 2002 and 2015, 32 patients were treated with repeat SRS for local recurrence of ≥ 1 brain metastasis following initial SRS treatment. The Kaplan-Meier method was used to estimate time-to-event outcomes including overall survival (OS), local failure, and radiation necrosis. Cox proportional hazards analysis was performed for predictor variables of interest for each outcome. Composite dose-volume histograms were constructed for each reirradiated lesion, and these were then used to develop a predictive dosimetric model for radiation necrosis. RESULTS Forty-six lesions in 32 patients were re-treated with a second course of SRS after local failure. A median dose of 20 Gy (range 14-22 Gy) was delivered to the tumor margin at the time of repeat SRS. Local control at 1 year was 79% (95% CI 67%-94%). Estimated 1-year OS was 70% (95% CI 55%-88%). Twelve patients had died at the most recent follow-up, with 8/12 patients experiencing neurological death (as described in Patchell et al.). Eleven of 46 (24%) lesions in 11 separate patients treated with repeat SRS were associated with symptomatic radiation necrosis. Freedom from radiation necrosis at 1 year was 71% (95% CI 57%-88%). Analysis of dosimetric data revealed that the volume of a lesion receiving 40 Gy (V40Gy) was the most predictive factor for the development of radiation necrosis (p = 0.003). The following V40Gy thresholds were associated with 10%, 20%, and 50% probabilities of radiation necrosis, respectively: 0.28 cm3 (95% CI 3%-28%), 0.76 cm3 (95% CI 9%-39%), 1.60 cm3 (95% CI 26%-74%). CONCLUSIONS Repeat SRS appears to be an effective salvage option for patients with brain metastases experiencing local failure following initial SRS treatment. This series demonstrates durable local control and, although rates of radiation necrosis are significant, repeat SRS may be indicated for select cases of local disease recurrence. Because the V40Gy is predictive of radiation necrosis, limiting this value during treatment planning may allow for a reduction in radiation necrosis rates.

Prediction of new brain metastases after radiosurgery: validation and analysis of performance of a multi-institutional nomogram

Stereotactic radiosurgery (SRS) without whole brain radiotherapy (WBRT) for brain metastases can avoid WBRT toxicities, but with risk of subsequent distant brain failure (DBF). Sole use of number of metastases to triage patients may be an unrefined method. Data on 1354 patients treated with SRS monotherapy from 2000 to 2013 for new brain metastases was collected across eight academic centers. The cohort was divided into training and validation datasets and a prognostic model was developed for time to DBF. We then evaluated the discrimination and calibration of the model within the validation dataset, and confirmed its performance with an independent contemporary cohort. Number of metastases (≥8, HR 3.53 p = 0.0001), minimum margin dose (HR 1.07 p = 0.0033), and melanoma histology (HR 1.45, p = 0.0187) were associated with DBF. A prognostic index derived from the training dataset exhibited ability to discriminate patients’ DBF risk within the validation dataset (c-index = 0.631) and Heller’s explained relative risk (HERR) = 0.173 (SE = 0.048). Absolute number of metastases was evaluated for its ability to predict DBF in the derivation and validation datasets, and was inferior to the nomogram. A nomogram high-risk threshold yielding a 2.1-fold increased need for early WBRT was identified. Nomogram values also correlated to number of brain metastases at time of failure (r = 0.38, p < 0.0001). We present a multi-institutionally validated prognostic model and nomogram to predict risk of DBF and guide risk-stratification of patients who are appropriate candidates for radiosurgery versus upfront WBRT.

A Phase II Clinical Trial of CPI-613 in Patients with Relapsed or Refractory Small Cell Lung Carcinoma.

Background Small cell lung cancer (SCLC) is a common lung cancer which presents with extensive stage disease at time of diagnosis in two-thirds of patients. For treatment of advanced disease, traditional platinum doublet chemotherapy induces response rates up to 80% but with few durable responses. CPI-613 is a novel anti-cancer agent that selectively inhibits the altered form of mitochondrial energy metabolism in tumor cells. Methods We evaluated CPI-613 with a single-arm, open-label phase II study in patients with relapsed or refractory SCLC. CPI-613 was given at a dose of 3,000 mg/m2 on days 1 and 4 of weeks 1–3 of 4 week cycle. The primary outcome was response rate as assessed by CT imaging using RECIST v1.1 criteria. Secondary outcomes were progression-free survival (PFS), overall survival (OS), and toxicity. Twelve patients were accrued (median age 57yo) who had previously received between 1 and 4 lines of chemotherapy (median 1) for SCLC with a treatment-free interval of less than 60 days in 9 of the 12 patients. Results No complete or partial responses were seen. Ten patients (83%) progressed as best response and 2 (17%) were not evaluable for response. Median time to progression was 1.7 months (range 0.7 to 1.8 months). Eleven patients (92%) died with median overall survival of 4.3 months (range 1.2 to 18.2 months). The study was closed early due to lack of efficacy. Of note, three out of three patients who progressed after CPI-613 and were subsequently treated with standard topotecan then demonstrated treatment response with survival for 18.2, 7.4, and 5.1 months. We conducted laboratory studies which found synergy in-vitro for CPI-613 with topotecan. Conclusions Single agent CPI-613 had no efficacy in this study. Further study of CPI 613 in combination with a topoisomerase inhibitor is warranted.

The Effects of smoking status and smoking history on patients with brain metastases from lung cancer

There is limited data on the effects of smoking on lung cancer patients with brain metastases. This single institution retrospective study of patients with brain metastases from lung cancer who received stereotactic radiosurgery assessed whether smoking history is associated with overall survival, local control, rate of new brain metastases (brain metastasis velocity), and likelihood of neurologic death after brain metastases. Patients were stratified by adenocarcinoma versus nonadenocarcinoma histologies. Kaplan–Meier analysis was performed for survival endpoints. Competing risk analysis was performed for neurologic death analysis to account for risk of nonneurologic death. Separate linear regression and multivariate analyses were performed to estimate the brain metastasis velocity. Of 366 patients included in the analysis, the median age was 63, 54% were male and, 60% were diagnosed with adenocarcinoma. Current smoking was reported by 37% and 91% had a smoking history. Current smoking status and pack‐year history of smoking had no effect on overall survival. There was a trend for an increased risk of neurologic death in nonadenocarcinoma patients who continued to smoke (14%, 35%, and 46% at 6/12/24 months) compared with patients who did not smoke (12%, 23%, and 30%, P = 0.053). Cumulative pack years smoking was associated with an increase in neurologic death for nonadenocarcinoma patients (HR = 1.01, CI: 1.00–1.02, P = 0.046). Increased pack‐year history increased brain metastasis velocity in multivariate analysis for overall patients (P = 0.026). Current smokers with nonadenocarcinoma lung cancers had a trend toward greater neurologic death than nonsmokers. Cumulative pack years smoking is associated with a greater brain metastasis velocity.

Frailty assessment predicts toxicity during first cycle chemotherapy for advanced lung cancer regardless of chronologic age

BACKGROUND Improved assessment strategies are needed to individualize treatment for adults of all ages receiving palliative chemotherapy for non-small cell lung cancer (NSCLC). Our aim was to evaluate the utility of the Fried Frailty Index (FFI) and a cancer-specific geriatric assessment (GA) to predict chemotherapy toxicity and overall survival (OS). METHODS We conducted a multi-site pilot study of 50 patients with newly diagnosed advanced NSCLC, age ≥ 18 years. All participants received carboplatin AUC 6, paclitaxel 200 mg/m2 every 3 weeks. FFI and the GA were administered prior to chemotherapy. A GA toxicity risk score was calculated. Grade 3-5 toxicity was assessed during 1st two cycles of chemotherapy. OS was measured from chemotherapy initiation. Logistic regression and Cox proportional hazards models were fit to estimate the association between baseline characteristics and toxicity and OS respectively. RESULTS Among 50 participants, 48 received chemotherapy and were evaluable. The mean age was 68.5 y (range 42-86), 79% male, 85% KPS ≥80. The median OS was 8 months. Many (27%) met FFI criteria for frailty with ≥3 impairments. Impairments detected by the GA were common. In multivariable analyses both FFI ≥ 3 and GA toxicity risk score > 7 were independently associated with higher odds of toxicity (Odds ratio [OR] 7.0; 95% confidence interval [CI] 1.1-44.6 and OR 4.3; 95% CI 1.0-17.7, respectively) in first cycle chemotherapy. Neither score was associated with OS. CONCLUSIONS Frailty predicts chemotherapy toxicity during first cycle. Frailty assessment may inform toxicity risk regardless of chronologic age.

The number of prior lines of systemic therapy as a prognostic factor for patients with brain metastases treated with stereotactic radiosurgery: Results of a large single institution retrospective analysis

OBJECTIVES It is presently unknown whether patients with brain metastases from heavily pre-treated cancers have a significantly different prognosis than those with less pre-treatment. In this study we sought to identify whether the number of prior lines of systemic therapy are associated with clinical outcomes in patients with brain metastases who received stereotactic radiosurgery (SRS). PATIENTS AND METHODS Between July 2000 and July 2017, 377 patients with brain metastases were treated with upfront SRS. We performed a large, single institution retrospective analysis of these patients. Kaplan Meier analysis was used to estimate survival times. Competing risk analysis was used to estimate times to local failure (LF) and distant brain failure (DBF). Multivariate analysis was performed to estimate the hazard ratios (HRs) for overall survival (OS), neurologic and non-neurologic death for patients with 1, 2 and 3+ lines of prior systemic therapy. RESULTS Of the 1077 patients with brain metastases treated with SRS, 377 received prior systemic therapy with a median of 1 (range: 1-9) lines of prior therapy. Median OS was 8.70 months (95% CI, 7.9-9.5). Median OS for patients with 1 prior line of therapy, 2 prior lines of therapy and 3 or greater lines of therapy were 9.93-, 9.05-, and 6.18-months, respectively (log rank p = .04). Lines of therapy as a continuous variable was not associated with LF or DBF on competing risk analysis. The percentage of patients that died of neurological death was 36%. Greater prior lines of therapy (1 vs. 2 vs. 3 and greater) was associated with a greater likelihood of dying of non-neurologic death (grays p = .01), but was not associated with likelihood of dying of neurologic death (p = .57). CONCLUSION Lines of therapy are associated with OS and non-neurologic death but are not associated with neurologic death, LF or DBF.

Sociodemographic predictors of patients with brain metastases treated with stereotactic radiosurgery

Background Patient sociodemographic factors such income, race, health insurance coverage, and rural residence impact a variety of outcomes in patients with cancer. The role of brain metastasis at presentation and its subsequent outcomes have not been well characterized in this patient population. Results Multivariate analysis revealed that median income lower than