Likelihood Of Benefit Research Articles

Imaging of T cells in patients with recurrent glioblastoma

Immunotherapies including CAR-T cell therapies offer some new hope for treatment of various cancers. As with all therapies, individual patient optimization would be of great help to maximize the chance of success. Issues including: (I) earlier detection of aggressive cancers; (II) staging of the cancer to determine different sites of tumor involvement; (III) determination of likelihood of benefit from a given therapy; (IV) monitoring during or soon after completion of therapy to determine non-responders so that one can change to another therapeutic strategy early; (V) monitoring for recurrence of the cancer after initial treatment, are all in need of careful attention. For each of these approaches both in vitro diagnostics and in vivo imaging offer potential solutions for cancer diagnosis and management.

Abstract CT126: Soluble HLA-G and -E (sHLA-G/E) as potential biomarkers of clinical outcomes in patients (pts) with advanced, refractory squamous (SQ) NSCLC treated with nivolumab (NIVO): CheckMate 063

Abstract Introduction: NIVO is a fully human IgG4 programmed death-1 (PD-1) immune checkpoint inhibitor providing long-term survival with a favorable safety profile and QoL benefit, approved for previously treated advanced/metastatic NSCLC. Although the likelihood of benefit from NIVO appears correlated with PD-L1 expression in non-SQ NSCLC, pts without PD-L1 may also benefit; this trend is not seen in SQ NSCLC. As sHLA-G/E are immunosuppressive molecules, we hypothesized that baseline peripheral sHLA-G/E may be associated with NIVO outcomes. Methods: CheckMate 063 is a phase 2, single-arm study of NIVO in SQ NSCLC pts who progressed on/after prior platinum-based doublet chemotherapy (PT-DC). Of 117 pts treated, 50 had evaluable baseline serum and archived tumor samples. sHLA-G and -E serum levels (‘low’ defined as <median; ‘high’ as ≥median) were measured by ELISA. Percent CD3+ and CD8+ T cells in tumor samples were evaluated by IHC. Results: Pts achieving PR or SD had lower baseline sHLA-G and -E (Table). Pts with longer OS had low sHLA-G and -E. Median OS was 8.6 vs 6.0 mo (HR 0.58 [0.31, 1.09]) in pts with low vs high sHLA-G, respectively; median OS was 13.6 vs 4.6 mo (HR 0.52 [95% CI 0.27, 0.97]) in pts with low vs high sHLA-E. Longest OS occurred in pts with both low sHLA-G and -E (n=14; median OS 15.1 mo [4.57, not reached]). No correlation was seen between baseline sHLA-G and -E levels (Spearman’s r=0.18; P=0.22). High peripheral sHLA-G and -E were negatively correlated with CD3/CD8+ T-cell tumor microenvironment infiltration (CD3+ r=-0.39 and -0.26; CD8+ r=-0.40 and -0.24, respectively). sHLA-G and -E were not associated with smoking and ECOG performance status. Table.Baseline sHLA-G and -E levels stratified by RECIST v1.1PR n=7SD n=3PD n=33bNE n=4PMedian sHLA-Ga4.687.5410.2921.140.41Median sHLA-Ea15.2511.3019.7330.830.39ang/mL; bn=32 for sHLA-ENE=non-evaluable; PD=progressive disease; PR=partial response; SD=stable disease Conclusion: Lower baseline sHLA-G and -E levels in NIVO pts with advanced, refractory SQ NSCLC were associated with improved OS. Further studies are warranted to determine if sHLA-G/E are prognostic or predictive biomarkers in SQ and non-SQ NSCLC. Citation Format: Vera Rebmann*, Wilfried E. Eberhardt*, Naiyer Rizvi, Scott J. Antonia, David Planchard, Federico Cappuzzo, Julien Mazières, Gérard Zalcman, Hervé Lena, Jürgen Wolf, Leora Horn, Thomas Stinchcombe, Grace Dy, Anne Blackwood-Chirchir, Chelsea Jin, William J. Geese, Suresh S. Ramalingam, *Authors contributed equally to the current work. Soluble HLA-G and -E (sHLA-G/E) as potential biomarkers of clinical outcomes in patients (pts) with advanced, refractory squamous (SQ) NSCLC treated with nivolumab (NIVO): CheckMate 063 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT126. doi:10.1158/1538-7445.AM2017-CT126

Extracorporeal Membrane Oxygenation for Severe Pediatric Respiratory Failure.

Extracorporeal membrane oxygenation (ECMO) was developed initially in the 1960s to support refractory respiratory failure in addition to the cardiac support inherent in a venoarterial bypass circuit. Early successes occurred predominantly in the neonatal population with subsequent randomized controlled trials and comprehensive reviews concluding therapeutic efficacy for ECMO in neonatal respiratory failure. In contrast, the evidence supporting ECMO for respiratory failure in children is less definitive. However, although pediatric randomized controlled trials have not been completed, sufficient evidence in support of ECMO as a beneficial therapy for pediatric respiratory failure exists. The acceptance of clinical utility and benefit from ECMO for pediatric ARDS and the trend toward increasing venovenous ECMO use have led to its inclusion in the Pediatric Acute Lung Injury Consensus Conference as a strongly agreed upon recommendation for severe pediatric ARDS. However, the Pediatric Acute Lung Injury Consensus Conference recommendations supporting the use of ECMO for pediatric ARDS highlight the lack of evidence-based selection criteria when determining ECMO candidacy in pediatric patients with ARDS. Ultimately, decisions to proceed with ECMO and the concomitant risk of potential life-threatening complications must consider multiple factors that balance potential risks and likelihood of benefit, pre-morbid conditions and impact on potential post-ECMO quality of life, candidacy for lung transplantation, and patient and family goals of care. This review will discuss ECMO for the support of pediatric respiratory failure, ventilator management during ECMO, considerations impacting timing of decannulation, and developing techniques.

Clinical utilization of Breast Cancer Index (BCI) for late recurrence risk assessment and prediction of extended endocrine therapy (EET) benefit in early stage HR+ breast cancer.

551 Background: Randomized trials demonstrated a modest (3-5%) absolute benefit from EET in patients (pts) with early stage HR+ breast cancer (BC), but also a risk of toxicities. BCI is a validated gene expression-based assay that provides 2 results: BCI Prognostic, based on the algorithmic combination of HoxB13/IL17BR (H/I ratio) and a set of proliferation-based genes, reports individualized risk of late distant recurrence (DR); BCI Predictive, based on H/I alone, reports a prediction of high vs low likelihood of benefit from EET. The objective of this study was to assess clinical and pathologic patient characteristics, prognostic and predictive assay results, and physician testing patterns in >14,000 clinical cases. Methods: The BCI Clinical Database for Correlative Studies is a de-identified database developed under an IRB approved protocol that contains >50 clinicopathologic and molecular variables from cases submitted for BCI in clinical practice. Clinicopathologic variables were abstracted from pathology reports, and were available for a subset of cases. Results: Across all pts (N=14,463), median age was 58.2y (range: 23-92y; 73.9% ≥50y). The majority were Stage I (47.3% IA, 3.5% IB, 29.1% IIA, 14.1% IIB, 6% III). Cases were 29%, 51%, and 20% Grade 1, 2, and 3, respectively. Most pts were ER+/PR+ (87.7%) or ER+/PR- (11.3%); 11.3% were HER2+. The majority of cases (55.7%) were ordered 4-6y postdiagnosis, with 23.1% >6y, 14.4% between 1-4y, and 6.8% <1y postdiagnosis. In LN- pts (n=3395), BCI Prognostic identified 50.6% as low risk for late DR vs 49.4% as high risk, while BCI Predictive (H/I) classified 41.0% as high vs 59.0% as low likelihood of benefit. In LN+ pts tested with the BCIN+ Prognostic algorithm (BCI + size/grade, n=818), 77.3% were classified as high risk vs 22.7% as low risk, while BCI Predictive (H/I) classified 44.6% and 55.4% as high vs low likelihood of benefit. Conclusions: Findings from this large cohort characterize utilization of BCI in clinical practice for pts with early-stage, HR+ BC. BCI stratification of pts with high risk and high likelihood of benefit from EET may facilitate selection of pts for prolonged regimens.

Correlation of Breast Cancer Index (BCI) prognostic and predictive results to Ki67 and tumor grade in early stage HR+ breast cancer.

e12075 Background: Markers of tumor proliferative status, e.g., Ki67 and grade (G), are prognostic for early distant recurrence (DR) in HR+ breast cancer and integrated in adjuvant chemotherapy decisions; however, their impact on late DR and extended endocrine therapy (EET) decisions is less clear. BCI is a genomic assay that provides 2 results: BCI Predictive, based on HoxB13/IL17BR (H/I ratio), reports a prediction of likelihood of benefit from EET; BCI Prognostic, based on the algorithmic combination of H/I and proliferation genes, reports risk of late DR. In this study, BCI results were examined within clinicopathologic risk categories based on Ki67 and G. Methods: The BCI Clinical Database for Correlative Studies is an IRB-approved de-identified database that contains > 50 clinicopathologic and molecular variables from cases submitted for BCI testing in clinical practice (N = 14,463). Clinicopathologic variables were abstracted from pathology reports, and were available for a subset of cases. High Ki67 was defined as ≥14%. Chi-squared tests were used to compare BCI results between Ki67 and G subgroups. Results: Analyses included 3395 LN- pts (median age 59.1y; 73% ≥ 50y). BCI Prognostic showed a wide distribution of individual risk assessments in pts with high or low Ki67. A greater proportion of pts with high Ki67 was classified by BCI as high risk of late DR compared to low Ki67 (68.2% vs 26.5%; P < 0.0001); however, substantial proportions of high Ki67 pts were classified as BCI low risk (31.8%) and pts with low Ki67 classified as BCI high risk (26.5%). Overall, there was a moderate correlation between individual BCI Scores and individual Ki67 scores (Correlation = 0.519). 45.5% of pts with high Ki67 were classified as High BCI Predictive (H/I) compared to 35.5% of pts with low Ki67 (p < 0.001). Both BCI Prognostic and BCI Predictive (H/I) classified increasing proportions of pts as high risk or high benefit with increasing G (P < 0.0001). Conclusions: These findings help characterize differential stratification based on tumor biology vs Ki67/G for pts considering EET. While moderately correlated, both BCI Prognostic and BCI Predictive (H/I) identified distinct populations compared to Ki67 and G.

Breast Cancer Index (BCI) prognostic and predictive classification in older versus younger patients with early-stage HR+ breast cancer (BC) and correlation with clinical risk factors.

546 Background: Older patients with HR+ BC may present distinct challenges for treatment decision-making. BCI is a validated gene expression assay for pts with early stage HR+ BC that provides 2 results: BCI Predictive, based on HoxB13/IL17BR (H/I ratio), reports a prediction of likelihood of benefit from extended endocrine therapy (EET); BCI Prognostic, based on the combination of H/I and proliferation-based genes, reports individualized risk of late distant recurrence (DR). Here, the predictive and prognostic value of BCI results across the aging spectrum ( < 64y, 65-74y, ≥75y) and correlation with clinical risk factors were examined. Methods: The BCI Clinical Database for Correlative Studies is an IRB-approved de-identified database that contains > 50 clinicopathologic and molecular variables from cases submitted for BCI in clinical practice (N = 14,463). Clinicopathologic variables were abstracted from pathology reports, and were available for a subset of cases. Chi-squared tests were used to compare BCI results between age groups and clinical subsets. Results: Analyses included LN- pts (N = 3,395): median age 59.1y; 5.5% ≥75y (N = 188), 24.0% 65-74y (N = 814), 70.5% ≤64y (N = 2,393). BCI Prognostic had a wide distribution of individual risk assessments in all age groups. The proportion of pts classified as high risk was similar between age groups (48.4%, 48.4% and 49.8% in ≥75y, 65-74y and ≤64y; p = 0.76). The proportion of pts with high risk results increased with increasing tumor size and grade in all age groups (P < 0.05 for all). Notably, in pts ≥75y, BCI identified 31.9% of T1a/b and 21.1% of Grade 1 tumors as high risk of late DR. BCI Predictive (H/I) also identified similar proportions as High H/I across age groups (42.0%, 41.8%, and 40.6% in ≥75y, 65-74y, and ≤64y; p = 0.81). Similar proportions of pts ≥75y were identified as high H/I across size and grade subsets (P = 0.702, P = 0.193, respectively). Conclusions: BCI identifies pts with high risk disease and who may benefit from EET across the aging spectrum. Individualized decisions for EET also must include life expectancy, competing comorbidities and potential toxicities from therapy.

Variable outcomes of medial meniscectomy in middle aged and older patients after 2 to 8 years

Objectives:To review midterm results of arthroscopic medial meniscectomy in patients over the age of 40.Methods: Retrospective observational series.All 354 patients over 40 years of age (after exclusion criteria) who underwent medial meniscectomy by a single surgeon for clinical and MRI correlated medial meniscal tears, having failed conservative treatment, between 2009 and 2014 were sent a questionnaire. Completed questionnaires from 179 patients at an average follow up of 52 ± 15 months (range, 20-79) were analysed.Results:The average time to maximum recovery was longer than expected at 5.6 ± 6 months (range 0.5-36). 74% (133) felt they were largely or completely relieved of symptoms, but, as predicted from past experience, 5% (8) were worse post-operatively. Symptoms became worse in the follow-up period in another 26% (47). 11% (20) had further surgery (15 to TKR). 9% (17) preferred to have left the knee alone in retrospect. Final WOMET and Tegner-Lysholm scores showed overall fair results (36% excellent, 17% good, 22% fair, 25% poor.)Conclusion:Medial meniscectomy in the middle aged and elderly remains controversial, with some claiming that it is no better than placebo, and possibly harmful. This data should provide guidance in counselling patients regarding the risks, and likelihood of benefit, from such surgery, and has led to the authors using more rigorous selection criteria. Prospective studies are needed.

Abstract P2-09-15: A multi-institutional, prospective study of incorporating the genomic platform breast cancer index as a tool for decision-making regarding extension of adjuvant endocrine therapy

Abstract Background: Extending adjuvant endocrine therapy (AET) for hormone responsive breast cancer (HRBC) from 5 to 10 years is beneficial for many in preventing late relapse. Current decision-making regarding extension relies on a decision-making process that weighs non-personalized recurrence risks against risks and benefits of extended AET. The Breast Cancer Index (BCI, BioTheranostics Inc) has been validated to quantify the risk of late recurrence and to predict likelihood of benefit from AET extension based on an individual's tumor genomic profile. The purpose of this study was to conduct a multi-institutional study to prospectively assess the impact of BCI i) on provider's recommendation using the BCI results; 2) the confidence with decision-making; and 3) patient's satisfaction regarding extension of AET. Methods: Patients with stage I-III HRBC treated at Yale Cancer Center and University of Pittsburgh Medical Center (UPMC), who had completed at least 3.5 years of AET were eligible. BCI was performed on FFPE samples from the original tumor sample (bioTheranostics Inc.). Patients and physicians completed pre- and post-test questionnaires examining preferences for extending AET, patients also completed anxiety and decision-conflict surveys. Results: 140 patients [mean age 61, 80% postmenopausal, 73% stage I] were included. No extended AET was recommended for 35.3% patients' pre-testing. Reasons physicians did not recommend extended AET were perceived low risk of recurrence (87%), risk of osteoporosis (25%) and side effects (13%). Extended therapy was recommended for 65.7% patients pre-testing. Integration of BCI resulted in a change in physician treatment recommendation in 29% of patients. The recommendation for no extended AET rose to 48% and recommendation for extended AET dropped to 52% (OR=1.76 95% CI 1.08-2.85; p=.003). Of the recommendations that changed (N=41), the majority (73%) was for not extending endocrine therapy. However, 27% of recommendations were to extend endocrine therapy because of high risk or high likelihood of benefit results. More physicians felt strongly confident in their recommendation after the test result (26.4%) than before (9.3%) (OR= 3.5 95% CI 1.77-6.95; p<.0001). Satisfaction of decision increased in 23% of patients (OR=2.72 95% CI 1.66-4.46; p<.0001). Patient reported concerns including the cost, safety and benefit of extended AET decreased from pre- to post-testing (p=.025; p<.0001; p=.0012 respectively) Conclusions: Overall, incorporation of BCI into clinical practice resulted in significant changes in physician recommendations regarding AET duration, with the majority of recommendations for no extended AET. Physicians reported increased confidence for their recommendation when incorporating the test result. There was also a significant increase in patient satisfaction and decrease in patient reported concerns regarding cost, safety and benefit of extended AET. The BCI is a tool that could be incorporated into decision-making algorithms to enhance physician confidence and patient satisfaction with recommendations for extending AET. Citation Format: Sanft T, Berkowitz A, Schroeder B, Hatzis C, Schnabel C, Aktas B, Brufsky A, Pusztai L, vanLonden GJ. A multi-institutional, prospective study of incorporating the genomic platform breast cancer index as a tool for decision-making regarding extension of adjuvant endocrine therapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-09-15.

Abstract 80: Left Atrial Structural and Functional Parameters in Ischemic Stroke Patients Show Differences in Cardioembolic versus Embolic Strokes of Unknown Source (ESUS) and Other Determined Causes: Rethinking Whether ESUS Patients Should be Treated as Cardioembolic Equivalents

Background: The role of anticoagulation in patients with embolic strokes of unknown source (ESUS) remains controversial. Left atrial (LA) structural and functional parameters on transthoracic echocardiography (TTE) may predict ESUS patients who are likely to develop subsequent paroxysmal atrial fibrillation (PAF). Hypothesis: LA parameters in ESUS patients will be similar to cardioembolic (CE) stroke patients and different from patients with strokes due to other determined cause (ODC). Methods: Patients admitted to a stroke center from June 1 to November 30, 2015 with acute ischemic stroke were included in this analysis. Baseline characteristics and results of inpatient diagnostic workup including neuroimaging, echocardiography, and cardiac telemetry were reviewed retrospectively to classify patients into three subtypes: CE, ODC or ESUS. LA diameter, LA volume index (LAVI), mitral valve early (MV E) and late filling peak (MV Peak A) velocities were compared between the 3 subtypes. Results: Of 131 patients (mean age 67 ± 16, 47% female, 45% white), 35 (27%) were classified as CE, 62 (47%) ODC and 34 (26%) ESUS. Baseline characteristics were similar between groups except that ODC patients were less likely to be female than CE and ESUS patients (p=0.05). LAVI, MV E and MV Peak A were all significantly different in CE compared with ODC and ESUS patients (p<0.05), with LA diameter showing a trend toward significance (p=0.058) (Figure). ESUS patients had LA diameter, LAVI, MV E and MV Peak A that were more similar to ODC than CE patients. Conclusions: LA structural and functional parameters among CE patients in our cohort were significantly different from those of ESUS and ODC patients, suggesting that ESUS patients may have lower risk of AF (and therefore lower likelihood of benefit from preemptive anticoagulation). Our study suggests that ESUS patients may benefit from long-term cardiac monitoring prior to initiation of anticoagulation therapy.

P2Y12 Inhibitor Pre-Treatment in Non-ST-Elevation Acute Coronary Syndrome: A Decision-Analytic Model.

Current guidelines recommend initiation of a P2Y12 inhibitor for all patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) at the time of diagnosis (pre-treatment); however, there are no randomized trials directly comparing pre-treatment with initiation at the time of angiography to support this practice. We explore clinical and institutional parameters potentially associated with benefit with this strategy in a decision-analytic model based on available evidence from randomised trials. A decision analysis model was constructed comparing three P2Y12 inhibitors in addition to aspirin in patients with NSTE-ACS. Based on clinical trial data, the cumulative probability of 30 day mortality, myocardial infarction (MI) and major bleeding were determined, and used to calculate the net clinical benefit (NCB) with and without pre-treatment. Sensitivity analysis was performed to assess the relationship between NCB and baseline ischemic risk, bleeding risk, time to angiography and local surgical revascularization rates. Pre-treatment with ticagrelor and clopidogrel was associated with a greater than 50% likelihood of providing a >1% increase in 30 day NCB when baseline estimated ischemic risk exceeds 11% and 14%, respectively. Prasugrel pre-treatment did not achieve a greater than 50% probability of an increase in NCB regardless of baseline ischemic risk. Institutional surgical revascularization rates and time to coronary angiography did not correlate with the likelihood of benefit from P2Y12 pre-treatment. In conclusion, pre-treatment with P2Y12 inhibition is unlikely to be beneficial to the majority of patients presenting with NSTE-ACS. A tailored assessment of each patient’s individual ischemic and bleeding risk may identify those likely to benefit.

Decision making and informed consent among participants in novel phase 1 trial designs.

e21548Background: Cancer patients in phase 1 clinical trials may be at risk of misunderstanding the objective of the trial (therapeutic misconception) or their own likelihood of benefit from partic...

The Immune Revolution in Gastrointestinal Tumours: Leading the Way or Just Following?

The encouraging results in immunotherapy for melanoma also led the way for translational and clinical research about immune-related mechanisms possibly relevant for gastrointestinal tumours. It is in fact now evident that the immune checkpoint modulation and in particular cell-mediated immune-response through programmed cell death-1 (PD-1) and the cytotoxic T-lymphocyte antigen-4 (CTLA4) receptors along with the regulatory T cells activity all have a relevant role in gastrointestinal cancers as well. This review aims to explore the state of the art of immunotherapy for gastrointestinal tumours, deepening recent scientific evidence regarding anti PD-1/PDL-1 and anti CTLA4 monoclonal antibodies, peptide based vaccine, DNA based vaccine, and pulsed dendritic cells, either alone or in combination with other antineoplastic medical therapy and locoregional treatments. Considering the non-negligible toxicity profile deriving from such a treatment approach, predictive biomarkers of response to immunotherapy in gastrointestinal cancer are also urgently needed in order to better select the patients' group with the highest likelihood of benefit.

Selection of Optimal Adjuvant Chemotherapy Regimens for Human Epidermal Growth Factor Receptor 2 (HER2) -Negative and Adjuvant Targeted Therapy for HER2-Positive Breast Cancers: An American Society of Clinical Oncology Guideline Adaptation of the Cancer Care Ontario Clinical Practice Guideline.

A Cancer Care Ontario (CCO) guideline on the selection of optimal adjuvant chemotherapy regimens for early breast cancer including adjuvant targeted therapy for human epidermal growth factor receptor 2 (HER2)-positive breast cancers was identified for adaptation. The American Society of Clinical Oncology (ASCO) has a policy and set of procedures for adapting clinical practice guidelines developed by other organizations. The CCO guideline was reviewed for developmental rigor and content applicability. On the basis of the content review of the CCO guideline, the ASCO Panel agreed that, in general, the recommendations were clear and thorough and were based on the most relevant scientific evidence, and they presented options that will be acceptable to patients. However, for some topics addressed in the CCO guideline, the ASCO Panel formulated a set of adapted recommendations on the basis of local context and practice beliefs of the Panel members. Decisions regarding adjuvant chemotherapy regimens should take into account baseline recurrence risk, toxicities, likelihood of benefit, and host factors such as comorbidities. In high-risk HER2-negative populations with excellent performance status, anthracycline- and taxane-containing regimens are the standard of care. Docetaxel and cyclophosphamide for four cycles is an acceptable non-anthracycline regimen. In high-risk HER2-positive disease, sequential anthracycline and taxanes administered concurrently with trastuzumab or docetaxel, carboplatin, and trastuzumab for six cycles are recommended. An alternative regimen in a lower-risk, node-negative, HER2-positive population is paclitaxel and trastuzumab once per week for 12 cycles. Trastuzumab should be given for 1 year. Platinum salts should not be routinely administered in the adjuvant triple-negative population until survival efficacy data become available.

Abstract P5-08-10: The breast cancer index as a tool in decision making for adjuvant hormonal therapy in early luminal breast cancer: Initiation, withdrawal and continuance

Abstract Background: Most women with newly diagnosed breast cancer are of luminal type and will be offered 5-10 years of adjuvant endocrine therapy. Many women will not have a survival benefit from this therapy and 30% or more will struggle with side effects and quality of life issues. Breast Cancer Index (BCI) is a genomic biomarker for early-stage, ER+ breast cancer and has been validated to assess risk of late (5-10 yr) distant recurrence and predict likelihood of benefit from extended (>5y) endocrine therapy utilizing the HoxB13/IL17BR(H/I) ratio. H/I has also been shown to predict benefit from endocrine therapy in the early adjuvant setting. The objective of this study was to characterize the impact of BCI on endocrine therapy decision-making for early-stage breast cancer patients. Methods: Data was collected retrospectively from patients with early-stage luminal breast cancer treated at Breastlink who underwent BCI testing between 10/2014-5/2015. The impact of BCI test results were analyzed for 3 indications: 1) initiation of endocrine therapy for patients considering no adjuvant treatment; 2) patients 6 mo-4y post diagnosis struggling with side effects and desiring to discontinue endocrine therapy; and 3) patients beyond 4 years of adjuvant hormonal therapy deciding whether to extend therapy for an additional 5 years. Results: One hundred patients underwent BCI testing with median age 53 (range 35-77). The BCI assay was utilized in 14 cases at diagnosis, 54 cases at 6 mo-4y during therapy, and 32 cases at >4y post-diagnosis. In patients tested at time of diagnosis, 10/11 that were low risk for late recurrence and low likelihood of benefit from endocrine therapy chose not to initiate therapy, and 2/2 patients were high risk/high likelihood to benefit initiated therapy. One patient, a 72 year-old with low risk and high likelihood to benefit, declined therapy. In patients tested between 6 mo-4y on therapy, 30/30 patients were low risk and low likelihood of benefit chose to stop endocrine therapy, and 11/11 patients were high risk and high likelihood of benefit chose to continue. Of 7 patients that were low risk but high likelihood of benefit, 5 continued therapy. All 6 patients that were high risk but low likelihood of benefit chose to stop therapy. Of 32 patients tested after 4 years of adjuvant therapy, 13/13 were low risk and low likelihood of benefit chose to stop endocrine therapy at 5 years, and 8/8 were high risk and high likelihood of benefit chose to extend therapy to 10 years. All 5 patients that were high risk but low likelihood of benefit elected to stop, and 3/6 patients that were low risk but high likelihood to benefit extended therapy. In total, endocrine therapy treatment decision making aligned with predictive (H/I) results in 93/100 patients. Conclusion: The BCI test was instrumental in assisting almost all women in their decision to receive or maintain adjuvant hormonal therapy and 67% of women discontinued or declined hormonal therapy based on test results. All patients with high risk and high predictive benefit on BCI assay chose to pursue adjuvant endocrine therapy. Oncologists can use BCI in their algorithms of delivering personalized cancer care. Citation Format: Link JS, Buck LJ, Kapoor NS. The breast cancer index as a tool in decision making for adjuvant hormonal therapy in early luminal breast cancer: Initiation, withdrawal and continuance. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-08-10.

Abstract P5-08-03: Prognostic impact of the combined risk groups by breast cancer index and HOXB13/IL17BR ratio in hormonal receptor positive, node negative breast cancer: A TransATAC study

Abstract Background: Breast Cancer Index (BCI) is a gene expression-based assay that reports two distinct results: 1) BCI predictive based on HoxB13/IL17BR ratio (H/I), and 2) BCI prognostic based on an algorithm incorporating H/I with the Molecular Grade index (MGI). Both biomarkers have been validated independently in randomized trial cohorts. However, integrated results to better correlate recurrence risk with endocrine response have not been evaluated. The aim of this post-hoc analysis was to examine patient outcomes within BCI prognostic and predictive groups using the translational arm of the Arimidex, Tamoxifen, Alone or in Combination trial (TransATAC). Methods: Primary tumor samples (N=742) from hormonal receptor-positive, N0 breast cancer patients treated with 5 years of tamoxifen (TAM) or anastrozole (ANA) in the ATAC trial were examined. Kaplan-Meier analysis was used to examine the risk of distant recurrence (DR) in patient subgroups derived from BCI and H/I results. A separate series of clinical cases submitted for BCI testing (N=853) were analyzed to determine distribution of the combined BCI and H/I groups in clinical practice. Results: Summary of patient distribution across the 6 BCI clinical subgroups showed that a large number of patients (331/742, 45%) were BCI low risk with low likelihood of benefit, whereas 108/742 (15%) of patients with endocrine responsive disease (High H/I) were classified as BCI low risk (Table 1). Kaplan-Meier analysis demonstrated that patients classified as BCI low risk had a very similar 10-year risk of DR irrespective of H/I status (H/I low: 5.5% vs. H/I high: 4.0%), indicating that prognosis was largely determined by BCI vs H/I. Table 1: Distribution of BCI and H/I risk groups in TransATAC BCI: PrognosticH/I: PredictiveLow RiskIntermediate RiskHigh RiskTotalLow Likelihood3318717435 (59%)High Likelihood10895104307 (41%)Total439 (59%)182 (25%)121 (16%)742 In 853 node negative cases submitted for BCI clinical testing, the distribution of BCI and H/I risk groups were similar to that from the TransATAC cohort (Table 2). Table 2: Distribution of BCI and H/I risk groups in clinical cases submitted for BCI testing BCI: PrognosticH/I: PredictiveLow RiskIntermediate RiskHigh RiskTotalLow Likelihood36410523492 (58%)High Likelihood96107158361 (42%)Total460 (54%)212 (25%)181 (21%)853 Discussion: Both prognostic and predictive components reported from the BCI assay may be used to stratify patients into 6 clinical subgroups based on prognostic risk of distant recurrence and endocrine responsiveness. Findings from this analysis indicate that patients classified as BCI low risk, regardless of H/I status, had sufficiently low DR rates and identifies patients that may be adequately treated with 5 years of endocrine therapy. Citation Format: Zhang Y, Sestak I, Schroeder BE, Dowsett M, Cuzick J, Schnabel CA, Sgroi DC. Prognostic impact of the combined risk groups by breast cancer index and HOXB13/IL17BR ratio in hormonal receptor positive, node negative breast cancer: A TransATAC study. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-08-03.

Abstract P4-14-15: Pre-treatment stromal tumour-infiltrating lymphocytes (S-TILs) are correlated with complete response (CR) to chemotherapy (Chemo) plus trastuzumab (T) in HER2-positive (H+) metastatic breast cancer (MBC)

Abstract Background. We have previously reported that ChemoT produces durable (>5 years) CR in a minority of pts with H+MBC, prompting a search for predictive markers. Extensive lymphocytic infiltration of cancers is correlated with high levels of immune gene signatures. International consensus guidelines on TILs define "lymphocyte-predominant BC" at a threshold of S-TILs of 50-60% versus tumour cells. High levels of S-TILs has been correlated with improved outcome in HER2+ early stage BC pts treated with ChemoT. We investigated the degree of S-TIL infiltration in metastatic biopsies from pts with HER2+MBC prior to ChemoT, and attempted to determine whether S-TILs predicted CR in HER2+MBC. Methods. We searched a database of all pts with HER2+ MBC treated at our institution with anti-HER2 therapy over 15yrs to identify pts who achieved CR according to RECIST 1.0 criteria, which lasted for at least 6 months. We matched them with an equal number of pts from the database who were treated during the same period, but who had progressive (POD) or stable disease (SD) as best response to T. Pts must have at least one pre-treatment tumour sample available for S-TILs assessment, and adequate clinical and follow-up information. S-TILs (mononuclear cells including lymphocytes and plasma cells) contained within the boundaries of invasive tumour were identified on a representative haematoxylin and eosin stained slide and scored as a percentage of the stromal area alone, according to the International TILs Working Group 2014 methodology [Salgado R, 2015]. S-TILs were assessed specifically for this study by a senior pathologist who scored the samples and who was blinded to pts response and clinical details. Results. Out of 246 MBC pts registered in the HER2+ database we identified 31 CR pts with at least one available pre-treatment metastatic sample. A cohort of 31 matching POD-SD pts was randomly obtained from the same database. In 8 cases (7 CR / 1 POD-SD) S-TILs could not be assessed due to inadequate material, or for other technical reasons. The final study sample is 54 pts (24 CR / 30 POD-SD). Pts characteristics are as follows: median age (range): CR 55 (29-78) / POD-SD 56 (26-89), hormone receptor (HR) pos: CR 12 (50%) / POD-SD 18 (60%), De Novo MBC at diagnosis: CR 13 (54%) / POD-SD 8 (27%) [p<0.05]. All pts received chemotherapy with T (+ lapatinib in 3 pts as part of a clinical trial), and continued on T until POD. Pre-treatment S-TILs >50% were statistically significantly more frequent in CR (50% of pts) than POD/SD (20%) [chi-square p=0.02]. No statistically significant difference in the HR status was observed between the two groups (CR vs POD-SD) or between the high and low S-TILs pts. Conclusions. S-TILs >50% in the pre-treatment tumour biopsy of HER2+MBC were significantly correlated with subsequent CR to ChemoT, supporting the hypothesis that the immunological effects of T may play a role in determining response. Speculatively, S-TILs might identify pts with a higher likelihood of benefit from T. Further study of the potential role of S-TILs as predictors of T benefit are required. Citation Format: Gullo G, Quinn C, Zacchia A, Fennelly D, Defrein A, Ballot J, Zanoni D, Walshe J, Maltese M, McDermott E, Crown J. Pre-treatment stromal tumour-infiltrating lymphocytes (S-TILs) are correlated with complete response (CR) to chemotherapy (Chemo) plus trastuzumab (T) in HER2-positive (H+) metastatic breast cancer (MBC). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-14-15.

Abstract C168: A two stage prospective clinical trial with irofulven treatment targeting a selected subgroup of castration- and docetaxel resistant prostate cancer patients

Abstract Irofulven, a DNA damaging semi -synthetic analog of Illudin S (phytotoxin from Omphalotus illudins, jack-o'-lantern mushroom) which in the body is activated by prostaglandin reductase, has shown promising clinical activity in a range of cancer forms but the objective response rates were too low to justify further clinical development. Of particular interest is that irofulven may not be a substrate of the mdr-1 drug efflux pump and thereby potentially active in prostate cancer patients with acquired resistance to docetaxel. We have now developed an irofulven responsive predictor which is based on gene expression data by comparing associations between gene expression profiles and growth inhibition in a panel of cell lines treated with irofulven. A second step has included filtering the identified gene expression profile against mRNA expression from a collection of 3200 human tumors. Only genes being differentially expressed in the clinical tumor material were retained in the model. A total of 205 mRNA's were selected for the final irofulven responsive profile. The profile can be converted to a single score of predicted irofulven responsiveness. We are now initiating a prospective clinical trial (Simon's two stage design) in selected patients with castration - and docetaxel resistant prostate cancer and with a favorable irofulven responsive profile. We are screening 600 prostate cancer samples (FFPE tissue) in order to select the 10% of patients with the highest likelihood of benefit from irofulven treatment. Primary end-points are objective response rate and changes in serum PSA. Citation Format: Steen Knudsen, Thomas Jensen, Anker Hansen, Ulla Buhl, Annie Rasmussen, Bruce Pratt, Arun Asaithambi, Nils Brünner, Peter Buhl Jensen. A two stage prospective clinical trial with irofulven treatment targeting a selected subgroup of castration- and docetaxel resistant prostate cancer patients. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C168.

Prospective study of the decision-making impact of the Breast Cancer Index in the selection of patients with ER+ breast cancer for extended endocrine therapy.

538 Background: The Breast Cancer Index (BCI) has been validated to quantify an individualized risk of late recurrence and to predict likelihood of benefit from extended endocrine therapy in ER+ early stage breast cancer.The purpose of this study was to prospectively assess the impact of BCI i) to change treatment recommendations regarding extended endocrine therapy, and ii) to examine its effects on patient anxiety and decision conflict. Methods: Patients with stage I-III, ER+ breast cancer treated at the Yale Cancer Center who completed at least 3.5 yrs of adjuvant endocrine therapy were prospectively enrolled over 6 months in 2014. BCI was performed on FFPE samples from the original biopsy (bioTheranostics Inc.). Patients and physicians completed pre- and post-test questionnaires. Patients completed the Traditional Decisional Conflict Scale (DCS) and State Trait Anxiety Inventory Form Y (STAI) pre- and post-test. Results: 100 patients[mean age 61y (45-88), 80% postmenopausal, 57% stage I] were included...

Clinicopathologic correlation and effect of Oncotype DX Recurrence Score on treatment decisions at a community-based academic cancer center.

e11511 Background: Oncotype DX, a 21 gene recurrence score (RS) is used to predict the likelihood of benefit from systemic chemotherapy in women with node-negative, estrogen receptor (ER) positive ...

The FOCUS4 design for biomarker stratified trials.

Randomised clinical trials (RCTs) remain the gold standard of evidence for the benefit of new therapeutics but standard designs fit awkwardly with key developments in biomarker-stratified drug development. Firstly, the unprecedented number of new agents being developed in oncology (usually with specific targets for which there may be predictive biomarkers) mandates a need for new trial designs that are more efficient in screening out new agents with modest likelihood of benefit, concentrating resources on the most promising ones. The multi-arm multi-stage (MAMS) design developed some years ago addresses this need. Secondly, biomarker-stratified trials, when tackled one biomarker/drug pairing at a time, are inherently highly inefficient. The FOCUS4 trial design was developed to overcome this problem, using a platform that incorporates multiple parallel biomarker-stratified RCTs in individual cohorts, and capable of adapting its design in response to developing evidence.