Differential Survival Benefit Research Articles

Abstract 4137009: Treating Elderly Cardiogenic Shock Patients with a Microaxial Flow Pump; Is It DANGERous?

Background: The Danish German Cardiogenic Shock trial (DanGer Shock) recently showed a reduction in all-cause mortality when treating selected patients with ST-segment elevation myocardial infarction (STEMI) and cardiogenic shock with a microaxial flow pump (mAFP). Whether there is an age-related differential survival benefit is unknown. Objective: To assess the influence of age on 180-day all-cause mortality in patients with STEMI and cardiogenic shock randomized in DanGer Shock. Methods: In DanGer Shock (an open-label, international, multicenter trial), 355 adult patients (aged ≥18 years with no upper age limit) with STEMI and cardiogenic shock were included and randomized to a mAFP (Impella CP) plus standard care or standard care alone. Patients were stratified in quartiles according to age, and logistic regression analyses were used to assess mortality according to age quartiles, and to evaluate whether age modified the treatment effect of the mAFP. Results: From lowest to highest quartile, patients’ ages ranged from 31-59, 60-69, 70-76, and 77-92, respectively. There were no differences in blood pressure, lactate level, left ventricular ejection fraction and shock severity across age groups. However, the proportion of females (41%) and the prevalence of hypertension (64%) was higher in patients aged ≥77 years (highest quartile), while more patients aged <60 years (lowest quartile) had been resuscitated before randomization. Mortality increased incrementally from the lowest quartile to the highest (31% vs. 47% vs. 61% vs. 73%, p log-rank <0.001), with an adjusted odds ratio for death at 180 days of 5.50 (95%CI 2.65-11.8, p<0.001) in the highest quartile compared to the lowest. Patients in the three lower quartiles had a lower absolute mortality at 180 days if randomized to the mAFP group, whereas patients in the highest quartile had a higher mortality if randomized to the mAFP group, p=0.028 for interaction, Figure. Conclusion: In patients with STEMI-related cardiogenic shock, the overall mortality increased with advancing age, and treatment benefit of the mAFP appeared to diminish in the eldest patients. (DanGer Shock, NCT01633502)

Cardiac MRI-Enriched Phenomapping Classification and Differential Treatment Outcomes in Patients With Ischemic Cardiomyopathy.

Significant controversy continues to confound patient selection and referral for revascularization and mitral valve intervention in patients with ischemic cardiomyopathy (ICM). Cardiac magnetic resonance (CMR) enables comprehensive phenotyping with gold-standard tissue characterization and volumetric/functional measures. Therefore, we sought to determine the impact of CMR-enriched phenomapping patients with ICM to identify differential outcomes following surgical revascularization and surgical mitral valve intervention (sMVi). Consecutive patients with ICM referred for CMR between 2002 and 2017 were evaluated. Latent class analysis was performed to identify phenotypes enriched by comprehensive CMR assessment. The primary end point was death, heart transplant, or left ventricular assist device implantation. A multivariable Cox survival model was developed to determine the association of phenogroups with overall survival. Subgroup analysis was performed to assess the presence of differential response to post-magnetic resonance imaging procedural interventions. A total of 787 patients were evaluated (63.0±11.2 years, 24.8% women), with 464 primary events. Subsequent surgical revascularization and sMVi occurred in 380 (48.3%) and 157 (19.9%) patients, respectively. Latent class analysis identified 3 distinct clusters of patients, which demonstrated significant differences in overall outcome (P<0.001). Latent class analysis identified differential survival benefit of revascularization in patients as well as patients who underwent revascularization with sMVi, based on phenogroup classification, with phenogroup 3 deriving the most survival benefit from revascularization and revascularization with sMVi (hazard ratio, 0.61 [0.43-0.88]; P=0.0081). CMR-enriched unsupervised phenomapping identified distinct phenogroups, which were associated with significant differential survival benefit following surgical revascularization and sMVi in patients with ICM. Phenomapping provides a novel approach for patient selection, which may enable personalized therapeutic decision-making for patients with ICM.

Somatostatin receptor 1 (SSTR1) expression as a potential predictive biomarker for response to androgen receptor signaling inhibitor (ARSI) therapy in metastatic castration-resistant prostate cancer (mCRPC).

180 Background: Overcoming ARSI resistance is an unmet need for mCRPC patients. Known resistance mechanisms include genetic alterations augmenting androgen receptor (AR) function (e.g., amplifications of the AR gene and its enhancer and AR mutations) and treatment-emergent evolution from an AR-driven to an AR-indifferent phenotype such as small cell neuroendocrine prostate cancer. Other mechanisms remain unexplored. Methods: To phenotype ARSI-resistant prostate cancer, we compared the RNA-seq profiles of paired metastatic biopsies from 31 mCRPC patients obtained before the initiation of first-line abiraterone or enzalutamide, and upon radiographic progression. The patient samples were obtained from two independent cohorts, the Stand Up To Cancer/Prostate Cancer Foundation (SU2C/PCF) West Coast Prostate Cancer Dream Team (WCDT) and a multi-institutional cohort from the Netherlands sequenced through the Hartwig Medical Foundation. We first evaluated RNA-seq data to identify the most differentially expressed genes and then performed survival analysis in the retrospective WCDT cohort (n=115, including 54 ARSI-naïve and 61 ARSI-experienced tumors) to assess the association between gene expression and overall survival, defined as the time interval from biopsy to death from any cause. Results: In the analysis of paired RNA-seq data from 31 mCRPC patients, SSTR1 was identified as the most significantly altered gene; SSTR1 expression was consistently decreased in post-treatment, ARSI-resistant tumors (log2[fold change]=-2.5, p=1.08×10-16). SSTR1 encodes somatostatin receptor 1, a G-protein coupled receptor that, when activated by the endogenous peptide hormone somatostatin or exogenous somatostatin analogues, mediates anti-proliferative, anti-migratory, and anti-secretory effects on target cells. Retrospective analysis in the 115 WCDT patients demonstrated that low SSTR1 expression was associated with worse overall survival ( p=0.047); ARSI treatment improved survival for patients with SSTR1-high (≥ median) tumors (HR=0.29, p=0.0002) more significantly than those with SSTR1-low (&lt; median) tumors (HR=0.67, p=0.17), with an interaction ( SSTR1 expression * ARSI treatment) towards statistical significance ( p=0.0598). A differential survival benefit of ARSI therapy with respect to SSTR1 expression was observed only among the 61 ARSI-experienced patients. Conclusions: SSTR1 expression is a potential predictive biomarker for response to ARSI in mCRPC, with higher SSTR1 expression predicting better response. This observation could be explained by an anti-tumor effect of SSTR1 signaling. Further work is warranted to prospectively validate these findings and to investigate SSTR1 as an actionable drug target to overcome ARSI resistance.

Efficacy of PD-(L)1 blockade monotherapy compared with PD-(L)1 blockade plus chemotherapy in first-line PD-L1-positive advanced lung adenocarcinomas: a cohort study

BackgroundSingle-agent PD-(L)1 blockade (IO) alone or in combination with chemotherapy (Chemotherapy-IO) is approved first-line therapies in patients with advanced lung adenocarcinomas (LUADs) with PD-L1 expression ≥1%. These regimens have not...

Comparative Analysis of First-Line FOLFOX Treatment With and Without Anti-VEGF Therapy in Metastatic Colorectal Carcinoma: A Real-World Data Study.

FOLFOX (leucovorin calcium [folinic acid], fluorouracil, and oxaliplatin) combined with or without anti-VEGF therapy represents one of the primary first-line treatment options for metastatic colorectal carcinoma (mCRC). However, there is limited comparative data on the impact of anti-VEGF therapy on treatment effectiveness, survival outcomes, and tumor location. This retrospective, comparative study utilized data from the AIM Cancer Care Quality Program and commercially insured patients treated at medical oncology clinics in the US. We analyzed 1652 mCRC patients who received FOLFOX, of which 1015 (61.4%) were also treated with anti-VEGF therapy (VEGF cohort). Patients in the VEGF cohort exhibited a higher frequency of lung (33% vs 23%; P < .001) and liver metastases (74% vs 62%; P < .001), underwent fewer liver surgeries prior to treatment (1.2% vs 3.6%; P = .002), and had a higher proportion of right-sided tumors (27% vs 18%; P = .001). Adjusted analysis revealed no significant difference in overall survival (OS) between patients treated with and without anti-VEGF (median survival: 25.4 vs 26.0 months; P = .4). FOLFOX-only treated patients experienced higher rates of post-treatment hospitalizations (22% vs 15%; P < .001). Notably, left-sided tumors treated with anti-VEGF showed a trend toward decreased OS (median survival: 26.8 vs 33months; P = .09). Our real-world data analysis suggests that the addition of anti-VEGF to FOLFOX offers limited and short-lived benefits in the context of mCRC and may provide differential survival benefit based on tumor sidedness.

Ten years survival benefit of CABG or PCI based on individual prediction

Abstract Background To compare the observed and individual predicted mortalities according to the SYNTAX score II 2020 (SSII-2020) in the all-comers SYNTAX population, and retrospectively assess the appropriateness of revascularization with percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) in patients with three vessel disease (3VD) and/or left main disease (LMCAD). Methods Internal and external validation of the SSII-2020 to predict 10-year all-cause death was performed in the respective randomized and registry SYNTAX populations. Differences in individual predicted mortalities following CABG or PCI were ranked and displayed with the observed mortalities. The proportions of screened patients deriving a survival benefit from CABG or PCI were determined retrospectively. Results A total of 2602 participants (as-treated population) were included in the randomized and registry cohorts. In the randomized cohort, all-cause mortality at 10 years, as an average treatment effect, was 23.8% (199/865) with CABG and 28.6% (249/901) with PCI, with a differential survival benefit of 4.6% (95% CI: 0.58% to 8.7%, log-rank p value=0.023). In the CABG and PCI registries, mortalities were 27.8% (167/644) and 55.4% (99/192), respectively. Calibration and discrimination of the SSII-2020 was helpful in CABG and PCI patients in the randomized and registry cohorts. In the PCI registry, the SSII-2020 underestimated mortality since specific comorbidities that entail high mortality are not included in the formula (C-index: 0.72, intercept: 0.38, slope: 0.66), whilst in the CABG registry, it predicted mortality with a helpful calibration and discrimination (C-index: 0.70, intercept: 0.00, slope: 0.76). The proportions of patients with a predicted survival benefit following CABG and PCI were respectively 78.3% (1383/1766) and 21.7% (383/1766) in the randomized cohort, and 82.4% (2143/2602) and 17.7% (459/2602) in the whole SYNTAX trial population. Conclusion In the randomized and registry cohort of this all-comers population with 3VD and/or LMCAD, there was reasonable agreement between the individual predicted and observed mortalities after CABG or PCI, such that the predicted 10-year survival benefit might be helpful in determining the appropriateness of each modality of revascularization. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): The SYNTAX Extended Survival study was supported by the German Foundation of Heart Research (Frankfurt am Main, Germany). The SYNTAX trial, during 0-5 years follow-up, was funded by Boston Scientific Corporation (Marlborough, MA, USA). Both sponsors had no role in the study design, data collection, data analyses, and interpretation of the study data, nor were involved in the decision to publish the final manuscript. The principal investigators and authors had complete scientific freedom.

Abstract 3420: Tgfbm3b is a natural germline genetic variant that modifies anti-tumor responses to anti-PD-1 immunotherapy through its action on the tumor microenvironment

Abstract Our goal for this study is to use a mouse genetics approach to identify host germline genetic variants that determine therapeutic responses to cancer immunotherapy (IMT) and to validate these findings in cancer patients treated with α-PD-1. The information gathered may lead to drug targets that potentiate IMT responses and genetic markers may contribute to risk scores for response to IMTs. Immune Checkpoint blockade (ICB) therapy leads to remarkable clinical responses, including highly durable complete responses in a fraction of patients. Consequently, α-PD-1/PDL-1 is now first-line therapy for treating melanoma and NSCLC (non-small cell lung carcinoma). However, most patients do not respond to α-PD-1 therapy, and few show systemic adverse effects. There is therefore an unmet need to develop biomarkers and drug targets that will potentiate therapeutic responses to ICBs. Firstly, we found that blockade of active TGFβ using therapeutic antibodies synergizes with α-PD-1 therapy to potentiate tumor rejection, thus, we hypothesized that variant genetic modifiers of TGFβ1 may influence outcomes of α-PD-1 therapy. By utilizing Tgfbm3b-C57BL/6 (Tgfbm3b-C57) mice carrying a genetic variation of TGFβ1 to study the anti-tumor response to IMT, we confirmed that Tgfbm3b-C57 potentiated anti-tumor responses to α-PD-1 and to combinatorial α-PD-1/α-TGFβ IMT with higher induction of CD8+ T cell-mediated anti-tumor cytotoxicity. The C57 allele contains gene Adam17 that encodes an amino acid variant, L613V, and a charge change at amino acid 113 (D113N). Protein ADAM17 is a sheddase that involves in TNFα biosynthesis and sheds the TGFβ type I receptor (TβRI) to attenuate TGFβ signaling. To understand the molecular function of the variants, the vectors encoding wildtype (NIH) ADAM17 that carries D113, L613 versus the variant (C57) ADAM17 that has N113, V613, are being transfected and tested for the action on a panel of ADAM17 substrates including TNFα and TβRI on NIH3T3 cell line. We are also investigating whether genetic variation within the syntenic human TGFBM3 locus confers differential survival benefit to patients after α-PD-1 therapy. We will confirm the genetic association of ADAM17 SNPs and screen the TGFBM3b locus from LPIN1 to HPCAL1, and YWHAQ to DDEF2. The dataset includes genome-wide association data from progression-free survival analysis of 2000 NSCLC patients following α-PD-1 therapy. The preliminary data from our initial cohort (n=862) of NSCLC patients on PD-1 inhibitors are currently being evaluated. By investigating the molecular and cellular mechanisms by which Tgfbm loci influence ICB outcomes and addressing the relevance to human cancer patients, this project not only addresses an important basic science question but may ultimately lead to novel biomarkers or drug targets that can improve IMT outcomes and reduce adverse effects. Citation Format: Szu-Ying Chen, Ons Mamai, Rosemary Akhurst. Tgfbm3b is a natural germline genetic variant that modifies anti-tumor responses to anti-PD-1 immunotherapy through its action on the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3420.

Lymph node ratio predicts efficacy of postoperative radiation therapy in nonmetastatic Merkel cell carcinoma: A population-based analysis.

After radical resection of a nonmetastatic Merkel cell carcinoma (M0 MCC), postoperative radiation therapy (RT) is recommended as it improves survival. However, the role of RT in specific subgroups of M0 MCC is unclear. We sought to identify whether there is a differential survival benefit from RT in specific M0 MCC patient subgroups. M0 MCC patients from the Surveillance, Epidemiology, and End Results (SEER) database registry were collected. The best prognostic age, tumor size, and lymph node ratio (LNR, ratio between positive lymph nodes and resected lymph nodes) cutoffs were calculated. The primary endpoint was overall survival (OS). A total of 5644 M0 MCC patients (median age 77 years, 62% male) were included: 4022 (71%) node-negative (N0) and 1551 (28%) node-positive (N+). Overall,2682 patients (48%) received RT. Age > 76.5 years, tumor size >13.5 mm, and LNR >0.215 were associated with worse OS. RT was associated with longer OS in the M0 MCC, N0, and N+ group and independently associated with a 25%, 27%, and 26% reduction in the risk for death, respectively. RT benefit on survival was increased in tumor size >13.5 mm in the N0 group and LNR >0.215 in the N+ group. No OS benefit from RT was observed in T4 tumors (N0 and N+ groups). RT was associated with improved survival in M0 MCC, irrespective of the nodal status. LNR >0.215 is a useful prognostic factor for clinical decision-making and for stratification and interpretation of clinical trials.

Differential Survival and Therapy Benefit of Patients with Breast Cancer Are Characterized by Distinct Epithelial and Immune Cell Microenvironments.

Extensive work in preclinical models has shown that microenvironmental cells influence many aspects of cancer cell behavior, including metastatic potential and their sensitivity to therapeutics. In the human setting, this behavior is mainly correlated with the presence of immune cells. Here, in addition to T cells, B cells, macrophages, and mast cells, we identified the relevance of nonimmune cell types for breast cancer survival and therapy benefit, including fibroblasts, myoepithelial cells, muscle cells, endothelial cells, and seven distinct epithelial cell types. Using single-cell sequencing data, we generated reference profiles for all these cell types. We used these reference profiles in deconvolution algorithms to optimally detangle the cellular composition of more than 3,500 primary breast tumors of patients that were enrolled in the SCAN-B and MATADOR clinical trials, and for which bulk mRNA sequencing data were available. This large data set enables us to identify and subsequently validate the cellular composition of microenvironments that distinguish differential survival and treatment benefit for different treatment regimens in patients with primary breast cancer. In addition to immune cells, we have identified that survival and therapy benefit are characterized by various contributions of distinct epithelial cell types. From our study, we conclude that differential survival and therapy benefit of patients with breast cancer are characterized by distinct microenvironments that include specific populations of immune and epithelial cells.

Beta-blockers provide a differential survival benefit in patients with coronary artery disease undergoing contemporary post-percutaneous coronary intervention management

Beta-adrenergic receptor blockers are used in patients with coronary artery disease (CAD) to reduce the harmful effects of excessive adrenergic activation on the heart. However, there is limited evidence regarding the benefit of beta-blockers in the context of contemporary management following percutaneous coronary intervention (PCI). We used the nationwide South Korea National Health Insurance database to identify 87,980 patients with a diagnosis of either acute myocardial infarction (AMI; n = 38,246) or angina pectoris (n = 49,734) who underwent PCI between 2013 and 2017, and survived to be discharged from hospital. Beta-blockers were used in a higher proportion of patients with AMI (80.6%) than those with angina (58.9%). Over a median follow-up of 2.2 years (interquartile range 1.2–3.3 years) with the propensity-score matching analysis, the mortality risk was significantly lower in patients treated with a beta-blocker in the AMI group (HR: 0.78; 95% CI 0.69–0.87; p < 0.001). However, the mortality risk was comparable regardless of beta-blocker use (HR: 1.07; 95% CI 0.98–1.16; p = 0.10) in the angina group. The survival benefit associated with beta-blocker therapy was most significant in the first year after the AMI event.

Effect of Myocardial Viability Assessed by Cardiac Magnetic Resonance on Survival in Patients With Severe Left Ventricular Dysfunction.

Background: Myocardial viability assessment in revascularization of ischemic heart failure remains controversial. This study evaluated the prognostic utility of cardiac magnetic resonance (CMR) late gadolinium enhancement (LGE) in ischemic heart failure.Methods and Results: This study retrospectively analyzed subjects with ischemic heart failure and left ventricular ejection fraction (LVEF) ≤35%, who underwent CMR at a single center in 2004–2014 before undergoing coronary artery bypass grafting (CABG) or optimal medical therapy (OMT). Analyses were stratified by treatment. Myocardial segments were deemed non-viable if LGE exceeded 50% wall thickness. Overall and anterior viability were assessed. Outcomes were all-cause mortality, cardiovascular (CV) mortality and major adverse CV events. Among 165 subjects (mean (±SD) age 57.5±8.5 years, 152 males), 79 underwent CABG and 86 received OMT. A greater number of non-viable segments was significantly associated with higher all-cause and CV mortality in the CABG group (adjusted hazard ratios 1.17 [95% confidence interval {CI} 1.01–1.37; P=0.04] and 1.25 [95% CI 1.01–1.56; P=0.045], respectively), but not in the OMT (P>0.05) group. Anterior wall viability did not affect outcomes.Conclusions: The extent of myocardial viability assessed by LGE appeared to identify patients with a differential survival benefit from CABG in this retrospective, small cohort study. These findings raise interesting hypotheses that need to be validated in larger prospective studies.

B2M Gene Expression Reflects an Immunologically Active Tumor Microenvironment in DLBCL

Introduction Interactions between tumor cells and the immune system play a critical role in regulating tumor development. Immune-based therapies have shown variable responses in diffuse large B-cell lymphoma (DLBCL) which suggests that the immune cell composition of the tumor microenvironment (TME) influences response to these agents. However, the key determinants of the immune TME are poorly understood. We have recently shown that indolent lymphomas can be stratified as immunologically 'hot' or 'cold' (Tobin et al J. Clin Oncol, in press) and sought to test for this in DLBCL. Also, given that beta-2-microglobulin (B2M) has a key role in antigen presentation and its loss is a frequent immune evasion mechanism in DLBCL, we determined the effect of B2M expression on the nature and magnitude of immune infiltration in the tumor microenvironment of DLBCL. Methods Ninety-seven de novo systemic DLBCL FFPE biopsies underwent targeted exon re-sequencing of B2M (Illumina) in addition to quantitative gene expression of Β2M, immune effector (CD4, CD8, CD56, CD137), immunosuppressive macrophage markers (CD68, CD163) and immune checkpoints (TIM3, LAG3, PD1 and PDL1) (Nanostring Technologies). B2M promoter methylation by mass array, immunohistochemistry for the above markers and high throughput T-cell receptor β sequencing (Adaptive Biotechnologies) were performed on a subset of cases. Genomic findings were validated in a whole exome and transcriptome cohort of approximately 1000 DLBCL samples (Reddy et al Cell 2017). Results Β2MMut were detected in 14/97 (14.4%) samples and had lower Β2M gene expression compared to Β2MWT (p = 0.0094) and all of these showed B2M protein loss. However, 29/40 (72%) of B2MWT samples tested also had B2M protein loss. There was no differential methylation of B2M promoter regions observed compared to lymph node controls. Results indicate that mechanisms other than mutation and methylation status contribute to loss of B2M surface expression and that a more comprehensive assessment of B2M expression within tumor tissues is achieved by B2M digital gene quantification. Consistent with this, there were no significant differences in expression of intra-tumoral immune markers between B2MMut and B2MWT tissues, whereas gene expression of B2M was significantly associated and positively correlated with the gene expression of CD4, CD8, CD56, CD137, CD68, CD163, PD1, PDL1, LAG3 and TIM3 (all p &lt;0.01) and with the protein expression of CD8, CD56, CD137, PDL1 and LAG3 (all p &lt;0.01), irrespective of their classification as an immune-effector, immune-checkpoint or macrophage markers. These observations are consistent with a co-ordinately regulated immune response, indicating an adaptive immune-checkpoint response to regulate immune-effector activation. In keeping with this, the housekeeper genes did not correlate with immune gene expression indicating that high or low co-ordinate expression of immune genes was not reflecting tissue RNA quality or quantity (Fig 1). Next, we tested the discovery cohort for relationships with the TCR repertoire. High B2M gene expression was significantly associated with reduced TCR diversity (p = 0.0101) compared to low B2M gene expression, suggesting that clonal T cell expansions are more likely with intact antigen presentation. The validation cohort also demonstrated that B2M gene expression correlated with immune cell infiltration and additionally showed that B2M positively correlated with the gene expression of HLA Class I//II molecules and a range of regulatory, transport and assembly molecules involved in the antigen presentation machinery pathway. However, no differential survival benefit was observed in patients with high versus low B2M. Conclusions In summary, digital gene expression is a robust measure of B2M quantification in the TME. Our data show that high B2M gene expression reflects an immunologically active or 'hot' tumor microenvironment in DLBCL characterised by higher levels of immune cell infiltration. These findings indicate that B2M gene expression level could be used as a biomarker of an active intra-tumoral immune response in DLBCL. Further studies are required to determine if B2M gene expression may have a role in stratifying the selection of patients in whom immune-based therapies are more likely to be effective. Disclosures Gould: NovoNordisk: Other: Travel funding - domestic flights to attend education, May 2018. Keane:MSD: Consultancy; BMS: Research Funding; Celgene: Consultancy; Gilead: Consultancy; Roche: Consultancy, Other: Travel Grant. Hertzberg:Takeda: Consultancy, Honoraria; MSD: Consultancy; Roche: Consultancy, Honoraria. Gandhi:Gilead: Honoraria, Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Other: Travel Support; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria.

Retrospective analysis of concurrent docetaxel and epirubicin neoadjuvant versus adjuvant chemotherapy: Which leads to better outcomes for different subtype breast cancer patients?

Different biological subtype breast cancers respond differently to neoadjuvant chemotherapy, but it is unknown whether neoadjuvant or adjuvant chemotherapy leads to different long-term survival in each specific subtype although equal outcomes have been reported in general population. This study sought to clarify whether the selection of either neoadjuvant or adjuvant chemotherapy was linked to a differential survival benefit based on breast cancer subtypes.A prospectively maintained breast cancer database was queried from 2000 to 2008. All patients with a diagnosis of stage II and III breast cancer who received neoadjuvant or adjuvant chemotherapy were identified, only patients receiving docetaxel and epirubicin (TA) regimen were included. Patients were divided according to the administration of neoadjuvant or adjuvant chemotherapy. The biological subtypes were determined by immunohistochemical tests. The outcomes between neoadjuvant and adjuvant chemotherapy were compared in each different subtype. Kaplan–Meier curves were generated, and the Cox model was used to estimate the association between death risk and chemotherapy timing while adjusting for potentially confounding factors. P values < .05 were considered statistically significant.Of the 406 patients included, 201 (49.5%) received neoadjuvant chemotherapy, and 205 (50.5%) received an adjuvant TA regimen. Patients with the HER2+ and TNBC subtypes showed significantly higher pCR rates than patients with luminal types (P < .05). In general population, the neoadjuvant and adjuvant chemotherapy groups showed little survival variance (HR=1.15, 95% confidence interval (CI) .69–1.91, P=.60). In luminal B-like patients, neoadjuvant chemotherapy led to worse overall survival (OS) than adjuvant therapy (HR=2.92, 95%CI 1.20 to 8.31, P = .02). In patients with the HER2+ subtype, neoadjuvant treatment corresponded to better OS (HR = .10, 95%CI .02–.58, P = .01). In contrast, patients with luminal A-like (HR = 1.14, 95%CI .53–2.43, P = .74) and TNBC disease (HR = 1.00, 95%CI .27–3.73, P = >.99) who underwent neoadjuvant chemotherapy showed equivalent OS when compared to patients undergoing adjuvant therapy.Neoadjuvant versus adjuvant chemotherapy results in a disparate impact on overall survival among patients with variant subtype breast cancer. When neoadjuvant chemotherapy was given, luminal B-like patients showed worse outcome, while patients with HER2+ disease had better OS. Prospective studies are necessary to determine and optimize the timing of chemotherapy for breast cancers with different molecular backgrounds.

Abstract 1741: Whole-transcriptome characterisation of NRAS and BRAF mutated primary melanomas associated with immune cell infiltration signatures and differential survival benefit

Abstract In 703 primary melanoma transcriptomes derived from formalin-fixed tumors removed from participants in the Leeds Melanoma Cohort, we used in silico methodology described by Bindea et al.1 to develop immune cell signatures. We showed these to be associated with survival2. There is some reported evidence that patients with NRAS mutated melanoma have a better response to checkpoint therapies3. Our aim was, therefore, to use the transcriptomic data to ask if immune cell infiltration (evidenced by the presence of the immune cell signature) differed between mutation subgroups. We saw that the survival benefit of the immune cell signature was strongest in wild-type (HR=0.31, P=3x10-5), intermediate in BRAF mutated tumors (HR=0.56, P=0.008) but absent in NRAS mutated tumors (HR=1.09, P=0.79). That is that even if the NRAS mutated tumors had a strong T cell signature that signature did not correlate with better survival. The results remained significant after adjusting for sex, tumor site, age at diagnosis, and AJCC stage. We observed no evidence of increased numbers of regulatory T cells (FOXP3), in NRAS mutated tumors, nor PDL1 or PD1 expression. The only difference in checkpoint molecule expression studied was a borderline lower expression of CTLA4 in the NRAS mutated tumors (P=0.09). Our data suggest that even when T cells invade NRAS mutated tumors some functional deficiency may be present in those tumors such that a survival benefit is not seen. Using genes significantly differentially expressed between NRAS and BRAF mutated tumor groups, we tested biological pathway enrichment using Reactome FIViz plugin in Cytoscape. The most enriched pathways in NRAS mutated melanomas were the PI3K (AKT3, NRAS) and mitochondrial translation (CHCHD1, PTCD3). In the BRAF mutated the most enriched were: direct P53 effectors (TGFA, IGFBP3), β-catenin independent WNT signaling (WNT5A) and MHC class I antigen processing (CYBA). A number of pathways related to cell adhesion involving GRIN1 were also identified. Others have reported that β-catenin signaling inhibits transcription of the chemokine CCL4 which reduces the trafficking of CD141+DC to melanomas and therefore T cell infiltration4. We have evidence from the β-catenin candidate transcriptomic analysis that primary melanomas without immune infiltration signatures have upregulated β-catenin but the comparison between transcriptomic patterns in NRAS and BRAF tumors did not suggest that β-catenin signaling was more active in NRAS mutated tumors. It may be that a different immunosuppressive mechanism is more common in NRAS mutated tumors than in others.

Serum Mass-Spectrometry Test in First Line Advanced Nsclc Patients Treated with Standard Chemotherapy Regimens

ABSTRACT Aim: The mass-spectrometry based serum test VeriStrat□ (VS) was shown to be prognostic in various therapies and predictive of differential overall survival (OS) benefit for erlotinib vs. chemotherapy (CT) in second line NSCLC setting. Performance of the test in CT is of clinical interest. We investigated the role of VS in 1st line advanced NSCLC patients (pts) treated with Cisplatin (Cis) or Carboplatin (Carbo) plus Pemetrexed (P). Methods: VS classification was available for 55 eligible stage IV,pts with non-squamous histology; pts were classified as VS Good (VSG) or VS Poor (VSP), VS testing of pretreatment serum samples was done blinded to clinical data. OS and progression-free survival (PFS) were analyzed by Kaplan-Meier method and compared using log-rank p-values; Cox models were used in multivariate analysis. Association with categorical variables was analyzed by Fisher's exact test. Results: 36 (65%) pts were classified as VSG and 19 (35%) as VSP. In the overall population, median PFS was 5.7 months (mo) for VSG vs.1.4 mo for VSP (hazard ratio (HR) 0.37 [0.19-0.72], p = 0.002 ); adjusted HR (AHR) 0.38 [0.17-0.86], p = 0.021). Median OS was 10.8 mo for VSG vs. 3.4 mo for VSP (HR 0.23 [0.11-0.51], p Conclusions: In Platinum-based doublet CT, VSP pts had much shorter PFS and OS than VSG. The behavior was similar in CisP and CarboP arms. Further research is needed to find alternative treatments to improve outcomes for VSP pts. ClinicalTrials.gov Identifier: NCT02055144. Disclosure: J. Grigorieva: stock options of Biodesix; H. Roder: stock options of Biodesix. All other authors have declared no conflicts of interest.

Serum mass-spectrometry test in first-line advanced NSCLC patients treated with standard chemotherapy regimens.

e19090 Background: The mass-spectrometry based serum test VeriStrat (VS) was shown to be prognostic in various therapies and predictive of differential overall survival (OS) benefit for erlotinib v...

Prognostic and Predictive Role of the VeriStrat Plasma Test in Patients with Advanced Non–Small-Cell Lung Cancer Treated with Erlotinib or Placebo in the NCIC Clinical Trials Group BR.21 Trial

We investigated the predictive and prognostic effects of VeriStrat, a serum or plasma-based assay, on response and survival in a subset of patients enrolled on the NCIC Clinical Trials Group, BR.21 phase III trial of erlotinib versus placebo in previously treated advanced non-small-cell lung cancer patients. Pretreatment plasma samples were available for 441 of 731 enrolled patients and were provided as anonymized aliquots to Biodesix. The VeriStrat test was performed in a Clinical Laboratory Improvement Act-accredited laboratory at Biodesix, Inc. (Boulder, CO). The results (Good, Poor) were returned to NCIC Clinical Trials Group, which performed all the statistical analyses. VeriStrat testing was successful in 436 samples (98.9%), with 61% classified as Good. VeriStrat was prognostic for overall survival in both erlotinib-treated patients and those on placebo, independent of clinical covariates. For VeriStrat Good patients, the median survival was 10.5 months on erlotinib versus 6.6 months for placebo (hazard ratio 0.63, 95% confidence interval 0.47-0.85, p = 0.002). For VeriStrat Poor patients, the median survival was 4 months for patients receiving erlotinib, and 3.1 months for placebo (hazard ratio: 0.77, 95% confidence interval 0.55-1.06, p = 0.11). VeriStrat was predictive for objective response (p = 0.002), but was not able to predict for differential survival benefit from erlotinib (interaction p = 0.48). Similar results were found for progression-free survival. We were able to confirm that VeriStrat is predictive of objective response to erlotinib. VeriStrat is prognostic for both OS and progression-free survival, independent of clinical features, but is not predictive of differential survival benefit versus placebo.

Association of left ventricular mechanical dyssynchrony with survival benefit from revascularization: a study of gated positron emission tomography in patients with ischemic LV dysfunction and narrow QRS

LV mechanical dyssynchrony (LVMD) is a risk marker in narrow QRS cardiomyopathy, but its association with treatment outcome is not well defined. We determined the incremental prognostic value of LVMD in ischemic cardiomyopathy, and assessed its interaction with scar, myocardium in jeopardy and subsequent revascularization. Stress and rest (82)Rb gated PET were performed in 486 consecutive patients (66 ± 11 years of age, 82 % men, LV ejection fraction 26 ± 6 %) with ischemic cardiomyopathy and QRS <120 ms. LVMD was determined as the standard deviation (SD) of the regional time to minimum volume on phase analysis of the gated PET scan. A propensity score was determined to adjust for nonrandomized referral after imaging to coronary artery bypass grafting (CABG). In a Cox proportional hazards model used to determine the association between measures of LVMD and survival time, CABG was included as a time-dependent covariate and the use of an implantable cardiac defibrillator (ICD) after imaging was modeled as a stratification factor. Over 1.9 ± 1.4 years, 96 patients (20 %) underwent CABG and 108 (22 %) died. LVMD was a predictor of mortality (HR 1.16. 95 % CI 1.03;1.30, per 10° increase in phase SD, p = 0.02) after adjusting for baseline covariates, prior ICD use, the use of postimaging CABG, and other imaging data. There was a significant interaction between phase SD and CABG. Nested Cox models showed that LVMD carried prognostic information incremental to clinical variables, ejection fraction and CABG. LVMD is an independent predictor of all-cause mortality in ischemic cardiomyopathy, and may identify patients with a differential survival benefit from CABG versus medical therapy.

Effect of BRCA mutation on prognosis in patients with ovarian cancer: A systematic review and meta-analysis.

5066 Background: To investigate whether the germ-line mutations of BRCA 1 and 2 in patients with ovarian cancer are associated with disease outcome. Methods: A systematic search of the literature was performed using search terms related to BRCA, ovarian cancer and prognosis. Studies were considered eligible if they reported the outcome of ovarian cancer in patients with BRCA 1 and/or 2 mutations compared with patients with sporadic ovarian cancer or / and no BRCA mutation. Cohort and case-control designs were included. Pooled Hazard Ratios (HR) were estimated with fixed or random effects models, depending on between-studies heterogeneity. Results: Of 2,340 titles identified, 26 articles met the inclusion criteria. Of these, 6 studies were excluded from the analysis due to duplication of results (n=1) and lack of data to calculate HR (n=5). Patients with BRCA 1 or 2 mutations had better survival compared with control group both in cohort (HR: 0.58, 95% Confidence Interval (CI) 0.42-0.79, p-value 0.0005) and in case-control (HR: 0.65, 95% CI 0.45-0.93, p-value = 0.02) studies. When only patients with BRCA 1 mutation were analyzed, the survival benefit remained significant (HR: 0.67, 95% CI 0.53-0.85, p-value = 0.001). Furthermore, the differential survival benefit of the mutation groups was even more evident among patients with BRCA 2 mutation (HR: 0.43, 95% CI: 0.30-0.63, p-value &lt; 0.0001). A direct comparison of patients with BRCA 1 vs. BRCA 2 mutations (4 studies) revealed a significantly better survival for BRCA 2 mutation carriers (HR: 0.53, 95% CI: 0.33-0.85, p-value = 0.009). Conclusions: Our results confirm the hypothesis that BRCA status is a prognostic factor in patients with ovarian cancer. Based on these results, the use of BRCA status as a stratifying factor in therapeutic ovarian cancer trials seems to be fully justifiable. The stronger association between survival and BRCA 2 mutation, compared with BRCA 1, suggests a different nature of the dysfunction of these 2 genes.

Myocardial Viability and Survival in Ischemic Left Ventricular Dysfunction

The assessment of myocardial viability has been used to identify patients with coronary artery disease and left ventricular dysfunction in whom coronary-artery bypass grafting (CABG) will provide a survival benefit. However, the efficacy of this approach is uncertain. In a substudy of patients with coronary artery disease and left ventricular dysfunction who were enrolled in a randomized trial of medical therapy with or without CABG, we used single-photon-emission computed tomography (SPECT), dobutamine echocardiography, or both to assess myocardial viability on the basis of prespecified thresholds. Among the 1212 patients enrolled in the randomized trial, 601 underwent assessment of myocardial viability. Of these patients, we randomly assigned 298 to receive medical therapy plus CABG and 303 to receive medical therapy alone. A total of 178 of 487 patients with viable myocardium (37%) and 58 of 114 patients without viable myocardium (51%) died (hazard ratio for death among patients with viable myocardium, 0.64; 95% confidence interval [CI], 0.48 to 0.86; P=0.003). However, after adjustment for other baseline variables, this association with mortality was not significant (P=0.21). There was no significant interaction between viability status and treatment assignment with respect to mortality (P=0.53). The presence of viable myocardium was associated with a greater likelihood of survival in patients with coronary artery disease and left ventricular dysfunction, but this relationship was not significant after adjustment for other baseline variables. The assessment of myocardial viability did not identify patients with a differential survival benefit from CABG, as compared with medical therapy alone. (Funded by the National Heart, Lung, and Blood Institute; STICH ClinicalTrials.gov number, NCT00023595.).