Ulrich-Peter Rohr

Venous Thromboembolic Events With Chemotherapy Plus Bevacizumab: A Pooled Analysis of Patients in Randomized Phase II and III Studies

PURPOSE Thromboembolism is a major source of morbidity and mortality in patients with cancer. The contribution of anti-vascular endothelial growth factor therapy to these events remains controversial. PATIENTS AND METHODS Individual patient data were available for 6,055 patients in 10 randomized studies. Unadjusted and exposure-adjusted incidence of venous thromboembolisms (VTEs) was estimated for the overall population and by tumor type. Multivariate analysis was performed to identify risk factors for development of VTE. The safety of anticoagulant therapy in patients undergoing bevacizumab treatment was also examined. RESULTS There were no statistically significant increases in the unadjusted or exposure-adjusted incidences of all-grade VTEs for bevacizumab versus controls in the overall population or by tumor type. The unadjusted incidence in the overall population was 10.9% with bevacizumab versus 9.8% with controls (odds ratio, 1.14; 95% CI, 0.96 to 1.35; P = .13); the rate per 100 patient-years was 18.5 for bevacizumab and 20.3 for controls (rate ratio, 0.91; 95% CI, 0.77 to 1.06; P =.23). Incidences of grade 3 to 5 events were similar in both groups. Several risk factors for VTEs were identified, including tumor type, older age, poorer performance status, VTE history, and baseline oral anticoagulant use. No interactions between bevacizumab treatment and these factors were observed. For patients who had a VTE and received full-dose anticoagulation therapy, the risk of severe bleeding was low (< 1%) and unaffected by bevacizumab treatment. CONCLUSION The addition of bevacizumab to chemotherapy did not statistically significantly increase the risk of VTEs versus chemotherapy alone. The risk for VTEs is driven predominantly by tumor and host factors.

The Value of In Vitro Diagnostic Testing in Medical Practice: A Status Report

Background In vitro diagnostic (IVD) investigations are indispensable for routine patient management. Appropriate testing allows early-stage interventions, reducing late-stage healthcare expenditure (HCE). Aim To investigate HCE on IVDs in two developed markets and to assess the perceived value of IVDs on clinical decision-making. Physician-perceived HCE on IVD was evaluated, as well as desired features of new diagnostic markers. Methods Past and current HCE on IVD was calculated for the US and Germany. A total of 79 US/German oncologists and cardiologists were interviewed to assess the number of cases where: physicians ask for IVDs; IVDs are used for initial diagnosis, treatment monitoring, or post-treatment; and decision-making is based on an IVD test result. A sample of 201 US and German oncologists and cardiologists was questioned regarding the proportion of HCE they believed to be attributable to IVD testing. After disclosing the actual IVD HCE, the physician’s perception of the appropriateness of the amount was captured. Finally, the association between physician-rated impact of IVD on decision-making and perceived contribution of IVD expenditure on overall HCE was assessed. Results IVD costs account for 2.3% and 1.4% of total HCE in the US and Germany. Most physicians (81%) believed that the actual HCE on IVDs was >5%; 19% rated the spending correctly (0–4%, p<0.001). When informed of the actual amount, 64% of physicians rated this as appropriate (p<0.0001); 66% of decision-making was based on IVD. Significantly, more physicians asked for either additional clinical or combined clinical/health economic data than for the product (test/platform) alone (p<0.0001). Conclusions Our results indicate a poor awareness of actual HCE on IVD, but a high attributable value of diagnostic procedures for patient management. New markers should deliver actionable and medically relevant information, to guide decision-making and foster improved patient outcomes.

Girdin (GIV) Expression as a Prognostic Marker of Recurrence in Mismatch Repair-Proficient Stage II Colon Cancer.

Purpose: Prognostic markers that identify patients with stage II colon cancers who are at the risk of recurrence are essential to personalize therapy. We evaluated the potential of GIV/Girdin as a predictor of recurrence risk in such patients. Experimental Design: Expression of full-length GIV was evaluated by IHC using a newly developed mAb together with a mismatch repair (MMR)-specific antibody panel in three stage II colon cancer patient cohorts, that is, a training (n = 192), test (n = 317), and validation (n = 181) cohort, with clinical follow-up data. Recurrence risk stratification models were established in the training cohort of T3, proficient MMR (pMMR) patients without chemotherapy and subsequently validated. Results: For T3 pMMR tumors, GIV expression and the presence of lymphovascular invasion (LVI) were the only factors predicting recurrence in both training (GIV: HR, 2.78, P = 0.013; LVI: HR, 2.54, P = 0.025) and combined test and validation (pooled) cohorts (GIV: HR, 1.85, P = 0.019; LVI: HR, 2.52, P = 0.0004). A risk model based on GIV expression and LVI status classified patients into high- or low-risk groups; 3-year recurrence-free survival was significantly lower in the high-risk versus low-risk group across all cohorts [Training: 52.3% vs. 84.8%; HR, 3.74, 95% confidence interval (CI), 1.50–9.32; Test: 85.9% vs. 97.9%, HR, 7.83, 95% CI, 1.03–59.54; validation: 59.4% vs. 84.4%, HR, 3.71, 95% CI, 1.24–11.12]. Conclusions: GIV expression status predicts recurrence risk in patients with T3 pMMR stage II colon cancer. A risk model combining GIV expression and LVI status information further enhances prediction of recurrence. Further validation studies are warranted before GIV status can be routinely included in patient management algorithms. Clin Cancer Res; 22(14); 3488–98. ©2016 AACR.

Prognostic value of MACC1 and proficient mismatch repair status for recurrence risk prediction in stage II colon cancer patients: the BIOGRID studies

Background We assessed the novel MACC1 gene to further stratify stage II colon cancer patients with proficient mismatch repair (pMMR). Patients and methods Four cohorts with 596 patients were analyzed: Charité 1 discovery cohort was assayed for MACC1 mRNA expression and MMR in cryo-preserved tumors. Charité 2 comparison cohort was used to translate MACC1 qRT-PCR analyses to FFPE samples. In the BIOGRID 1 training cohort MACC1 mRNA levels were related to MACC1 protein levels from immunohistochemistry in FFPE sections; also analyzed for MMR. Chemotherapy-naïve pMMR patients were stratified by MACC1 mRNA and protein expression to establish risk groups based on recurrence-free survival (RFS). Risk stratification from BIOGRID 1 was confirmed in the BIOGRID 2 validation cohort. Pooled BIOGRID datasets produced a best effect-size estimate. Results In BIOGRID 1, using qRT-PCR and immunohistochemistry for MACC1 detection, pMMR/MACC1-low patients had a lower recurrence probability versus pMMR/MACC1-high patients (5-year RFS of 92% and 67% versus 100% and 68%, respectively). In BIOGRID 2, longer RFS was confirmed for pMMR/MACC1-low versus pMMR/MACC1-high patients (5-year RFS of 100% versus 90%, respectively). In the pooled dataset, 6.5% of patients were pMMR/MACC1-low with no disease recurrence, resulting in a 17% higher 5-year RFS [95% confidence interval (CI) (12.6%-21.3%)] versus pMMR/MACC1-high patients (P = 0.037). Outcomes were similar for pMMR/MACC1-low and deficient MMR (dMMR) patients (5-year RFS of 100% and 96%, respectively). Conclusions MACC1 expression stratifies colon cancer patients with unfavorable pMMR status. Stage II colon cancer patients with pMMR/MACC1-low tumors have a similar favorable prognosis to those with dMMR with potential implications for the role of adjuvant therapy.

Abstract 2778: Combination of DNA mismatch repair status and MACC1 expression in patients with stage II colon cancer: The BIOGRID studies

We have previously identified the gene Metastasis-Associated in Colon Cancer 1 (MACC1). MACC1 acts a prognostic biomarker for tumor progression, metastasis and patient survival for a broad variety of solid cancer types. Here we assessed if the MACC1 gene could separate stage II colon cancer patients with proficient mismatch repair (pMMR) into high- and low-risk groups who might benefit from or be spared adjuvant chemotherapy based on their prognosis. In the Charite 1 discovery cohort (n=61), MACC1 expression and MSI status were assayed by qRT-PCR in cryo-preserved tumors from CRC patients. MSS/MSI-low/MACC1-low tumors showed better survival vs. MSS/MSI-low/MACC1-high (Pl0.0001). Patients with MSS/MSI-low/MACC1-low tumors had a similar prognosis as patients with MSI-H tumors. The Charite 2 comparison cohort (n=40) was used to translate MACC1 qRT-PCR analyses to FFPE samples. MACC1 expression was significantly higher in metachronously metastasizing tumors linked to shorter relapse-free survival (RFS), independent of the tissue type analyzed (cryo-preserved or FFPE). Next we translated MACC1 mRNA levels from qRT-PCR to MACC1 protein levels from immunohistochemistry (IHC) by comparing them in consecutive FFPE tumor sections in the BIOGRID 1 training cohort (n=189) enriched for disease recurrence. Chemotherapy-naive patients with unfavorable pMMR status separated into MACC1-high and -low groups. Better RFS was seen in the pMMR/MACC1-low vs. pMMR/MACC1-high group using MACC1 mRNA and protein expression. pMMR/MACC1-low expression was seen in 12% and 8% of patients by qRT-PCR and IHC; interestingly, they had the same favorable prognosis as the deficient MMR (dMMR) group. Prognostic and predictive findings from BIOGRID 1 were confirmed in the independent BIOGRID 2 validation cohort (n=306) unenriched for recurrence. Better RFS was again seen in chemotherapy-naive patients in the pMMR/MACC1-low (6%) vs. pMMR/MACC1-high group. No patients with pMMR/MACC1-low phenotype had disease recurrence. Remarkably, pooling BIOGRID 1 and 2, 5-year RFS was 100% and thus significantly longer in the pMMR/MACC1-low vs. pMMR/MACC1-high group (P=0.037). Taken together, MACC1 expression, measured by qRT-PCR or IHC, differentiates patients with unfavorable pMMR status. Patients with stage II colon cancer and pMMR/MACC1-low tumor status have a similar favorable prognosis as those patients with dMMR status who might not benefit from adjuvant therapy. Citation Format: Ulrich-Peter Rohr, Pia Herrmann, Katharina Ilm, Hai Zhang, Sabine Lohmann, Astrid Reiser, Andrea Muranyi, Janice Smith, Susen Burock, Marc Osterland, Katherine Leith, Shalini Singh, Patrick Brunhoeber, Rebecca Bowermaster, Jeanne Tie, Michael Christie, Hui-Li Wong, Paul Waring, Kandavel Shanmugam, Peter Gibbs, Ulrike S. Stein. Combination of DNA mismatch repair status and MACC1 expression in patients with stage II colon cancer: The BIOGRID studies [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 2778. doi:10.1158/1538-7445.AM2017-2778

569PGIV AS A NOVEL PROGNOSTIC MARKER IN STAGE II COLON CANCER

ABSTRACT Aim: There is an evident unmet need to better define recurrence risk for patients with stage II colon cancer (CC), particularly those with mismatch repair proficient (pMMR) tumors, to determine the subgroup of patients that may benefit from adjuvant chemotherapy. GIV/Girdin is a novel metastasis associated protein that triggers tumor cell invasion by enhancing PI3K/AKT signaling downstream of multiple oncogenic receptors. We explored the potential of GIV as a prognostic marker in stage II CC. Methods: A MMR antibody panel and a GIV specific antibody were developed by Ventana and evaluated by immunohistochemistry (IHC) on a cohort of stage II CC from Melbourne (n = 192), enriched for patients with recurrent disease (n = 44, 25%). Log rank test was used to assess the association of GIV IHC expression status with the recurrence risk. Evaluation of alternative GIV scoring algorithms, combining staining intensity and percent staining, and statistical predictive modeling including the analysis of distant recurrence free survival (DRFS) was undertaken for the chemo-naive cases, stratified by MMR and AJCC tumor (T) status. The association between GIV IHC status and standard histopathologic criteria was also assessed. Results: The distribution of deficient MMR (dMMR) vs pMMR cases were 20.8% and 79.2%, respectively. Within the chemo-naive population (n = 103), expected associations between pathologic features and DRFS were observed, including pMMR vs dMMR (HR 4.12, p = 0.052), T4 vs T3 (HR 2.39, p = 0.055) and lymphovascular invasion (LVI) vs no LVI (HR 2.62, p = 0.021). GIV positivity, defined as >10% of tumor cells stained or any staining of 3+ intensity, was present in 45 (44.0%) of pMMR chemo-naive cases. For T3 pMMR chemo-naive cases (n = 91), GIV positivity was associated with significantly reduced DRFS (HR 2.49, p = 0.022). Adding LVI as an additional parameter to the algorithm for this group increased the HR to 4.74 (95% CI 1.90-11.85). Conclusions: GIV IHC expression status has been found to be associated with T3 disease, pMMR, and DRFS in an initial cohort of stage II CC. This exploratory diagnostic algorithm currently undergoes validation in two independent clinical stage II CC cohorts, with promising preliminary data. Disclosure: P. Waring: received research grant funding from F. Hoffmann-La Roche; B. Lafleur, A. Muranyi, S. Singh and P. Brunhoeber: Employee of Ventana Medical Systems, Inc., a member of the Roche Group; S. Hu, V. Teichgraber, U. Rohr, R. Ridder:. and K. Shanmugam: Employee of F. Hoffmann-La Roche Ltd. All other authors have declared no conflicts of interest.