Marker For Progression-free Survival Research Articles

NPY Gene Methylation in Circulating Tumor DNA as an Early Biomarker for Treatment Effect in Metastatic Colorectal Cancer.

Simple SummaryDespite several limitations, imaging is still the gold standard in evaluating the treatment effect in metastatic colorectal cancer, and the best response is often achieved several months after treatment start. The present study investigated methylated circulating tumor DNA (ctDNA) in the blood and found that a reduction in ctDNA after one treatment cycle was a better marker of progression-free survival than imaging. Furthermore, ctDNA increases in the blood before progression are visible on imaging, allowing for a change in treatment at an earlier time point. Methylated ctDNA is an early indicator of treatment benefit and a promising endpoint in clinical trials.Despite several limitations, the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) are still the gold standard in response evaluation of metastatic colorectal cancer (mCRC). The aim of the present study was to investigate hypermethylated neuropeptide Y circulating tumor DNA (meth-NPY) as an early biomarker for treatment effect and monitoring in 70 mCRC patients receiving first-line treatment in the FOLFOXIRI-Toco trial. Meth-NPY was analyzed using droplet digital PCR, and the response rate was defined as the fraction of patients converting from a baseline detectable level to an undetectable level after the first treatment cycle (responders). A significant increase in meth-NPY was defined as a value with no overlap between the 95% CI of the current and preceding measurement. Progression-free survival (PFS) was significantly longer in meth-NPY responders compared to non-responders, 10.1 and 7.6 months, respectively (p = 0.02, HR = 0.43). Patients with response according to RECIST 1.1 had a PFS of 10.1 compared to 7.3 months for non-responders (p = 0.17, HR = 0.65). A significant increase in meth-NPY was found with a median of 49 days before radiological progression. In conclusion, early meth-NPY response proved superior to response according to RECIST 1.1 with respect to predicting improved PFS. Meth-NPY is an early indicator of progression, allowing treatment reorientation at an earlier timepoint.

Characteristics and clinical outcome of high-risk multiple myeloma patients in Korea (KMM 1805).

Optimal treatments for multiple myeloma (MM) patients with high-risk cytogenetics must be determined, but subgroup features are not well-defined. We used real-world data from the Korean Myeloma Registry (KMR) to analyze the characteristics and clinical outcomes of newly diagnosed MM patients with ≥ 1 high-risk cytogenetic abnormality: Group 1: t(4;14) or t(14;16); Group 2: del(17p); Group 3: t(4;14)/del(17p) or t(14;16)/del(17p). Overall, 347 high-risk patients were identified (males, 48.7%; median age, 63years). Median progression-free survival (PFS) and overall survival (OS) were 19.0months (95% CI 17.0-20.0) and 50.0months (95% CI 37.0-61.0), respectively. PFS (p = 0.047) and OS (p = 0.020) differed significantly between groups. After stratification by transplant eligibility, PFS and OS were significantly poorer in Group 3 among transplant-eligible patients, and even poorer in those with gain(1q). Patients stratified by cytogenetic abnormality and revised International Staging System (R-ISS) had significantly different PFS (p < 0.001) and OS (p = 0.003), with the worst survival in R-ISS III/Group 3 (median OS 21.0months). Higher number of high-risk cytogenetic abnormalities was a negative prognostic marker for PFS and OS (p < 0.001). Real-world KMR data showed that risk factors for poor prognosis of MM patients included del(17p), R-ISS stage, and number of cytogenetic abnormalities.

Consolidation with Bortezomib, Lenalidomide and Dexamethasone Upgrades the Complete Remission Rate after Autologous Hematopoietic Cell Transplantation in Patients with Multiple Myeloma

Introduction : High-dose therapy (HDT) combined with autologous stem cell transplantation (ASCT) is a standard front-line treatment strategy for patients with newly diagnosed multiple myeloma (MM). Unfortunately, almost all the patients will eventually relapse, emphasizing the need for new treatment options or strategies to improve outcomes in these patients. A recent meta-analysis clearly demonstrated that post-transplant lenalidomide maintenance improves overall survival (OS), conflicting results were reported on the benefit of early post-transplant consolidation with bortezomib, lenalidomide, and dexamethasone (VRD). The aim of this study was to assess the effect of VRD consolidation on complete remission (CR) rate at Day100 post ASCT, a surrogate marker for progression free survival (PFS) and OS.Methods: This study was conducted at the American university of Beirut Medical Center, Lebanon. A total of 42 patients newly diagnosed with MM had received ASCT, followed by a total post-transplant treatment consisted of 2 cycles of VRD consolidation and maintenance lenalidomide. These patients were treated and followed between 2011 and 2016. All patients received pre-transplant bortezomib based induction. Of them, 17 (41%) patients had VRD triplet combination. The conditioning regimen consisted of high dose melphalan. The consolidation regimen consisted of bortezomib 1.3 mg/m2 I.V. (days 1, 8, 15 and 22 of each 28-day cycle), lenalidomide 25 mg orally daily for 21 days every 28 days, dexamethasone 20 mg total orally (days 1, 8, 15 and 22 of each 28-day cycle) for a total of 2 cycles. Patients and disease characteristics are summarized in table 1.Results: Median age at transplantation was 55 (41-75) years. Median time from diagnosis to transplant was 5 (3-49) months. The median number of days to reach an absolute neutrophil count more than 500/mm3 post-ASCT was 11 days. VRD consolidation therapy was initiated at a median of 59 (34-201) days from transplantation. In total, 40 (95%) patients completed 2 cycles of VRD without grade 3/4 adverse events. One patient could not receive bortezomib during cycle 2 because of severe peripheral neuropathy. All patients received maintenance with lenalidomide. At time of transplant, only 4 (10%) patients were in complete remission (CR), 25 (59%) patients in very good partial remission (VGPR), and 11 (26%) patients in partial remission. Day 30 evaluation post-transplant, 11 (26%) patients were in CR, 6 (14%) patients in VGPR. Importantly, assessment of disease status at day 100 post-transplant identified 17 (40%) patients in CR. After a median follow up of 26 months, the 2 years PFS was 81% and OS was 92.9%.Conclusion: VRD consolidation significantly upgrades the CR rate after ASCT in patients with MM. These encouraging findings need to be verified and confirmed in prospective randomized trials, establishing a new standard of post-transplant treatment in MM. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Markers of Prognosis for Early Stage Cervical Cancer Patients (Stage IB1, IB2) Undergoing Surgical Treatment.

BackgroundFor individuals with cervical cancer, large tumor volume, lymph node metastasis, distant metastasis, and parauterine infiltration are usually associated with a poor prognosis. Individuals with stage 1B1 and 1B2 cervical cancer usually do not have these unfavorable prognostic factors. Once the disease progresses, the prognosis becomes extremely poor. Therefore, investigating the prognostic markers of these cervical cancer patients is necessary for treatment.MethodsThis retrospective study included 95 cervical cancer patients treated with surgery. The patients were divided into progressor and non-progressor groups according to postoperative follow-up results. T-test (or Mann−Whitney U test), chi-squared test (or Fisher’s exact test) and receiver operating characteristic (ROC) curves were used to evaluate imaging, hematology, and clinicopathological index differences between the two groups. Cox analysis was performed to select the independent markers of progression-free survival (PFS) when developing the nomogram. Validation of the nomogram was performed with 1000 bootstrapped samples. The performance of the nomogram was validated with ROC curves, generated calibration curves, and Kaplan-Meier and decision curve analysis (DCA).ResultsCervical stromal invasion depth, lymphovascular space invasion (LVSI), human papilloma virus (HPV-16), Glut1, D-dimer, SUVmax and SUVpeak showed significant differences between the two groups. Multivariate Cox proportional hazard model showed SUVpeak (p = 0.012), and HPV-16 (p = 0.007) were independent risk factors and were used to develop the nomogram for predicting PFS. The ROC curves, Kaplan-Meier method, calibration curves and DCA indicated satisfactory accuracy, agreement, and clinical usefulness, respectively.ConclusionsSUVpeak level (≥7.63 g/cm3) and HPV-16 negative status before surgery were associated with worse PFS for patients with cervical cancer. Based on this result, we constructed the nomogram and showed satisfactory performance. Clinically, individualized clinical decision-making can be performed on patients based on this result.

Liquid biopsy reveals KLK3 mRNA as a prognostic marker for progression free survival in patients with metastatic castration-resistant prostate cancer undergoing first-line abiraterone acetate and prednisone treatment.

Circulating RNAs extracted from liquid biopsies represent a promising source of cancer‐ and therapy‐related biomarkers. We screened whole blood from patients with metastatic castration‐resistant prostate cancer (mCRPC) following their first‐line treatment with abiraterone acetate and prednisone (AA‐P) to identify circulating RNAs that may correlate with progression‐free survival (PFS). In a prospective multicenter observational study, 53 patients with mCRPC were included after they started first‐line AA‐P treatment. Blood was drawn at baseline, 1, 3, and 6 months after treatment initiation. The levels of predefined circulating RNAs earlier identified as being upregulated in patients with mCRPC (e.g., microRNAs, long noncoding RNAs, and mRNAs), were analyzed. Uni‐ and multivariable Cox regression and Kaplan–Meier analyses were used to analyze the prognostic value of the various circulating RNAs for PFS along treatment. Detectable levels of kallikrein‐related peptidase 3 (KLK3) mRNA at baseline were demonstrated to be an independent prognostic marker for PFS (201 vs 501 days, P = 0.00054). Three months after AA‐P treatment initiation, KLK3 could not be detected in the blood of responding patients, but was still detectable in 56% of the patients with early progression. Our study confirmed that KLK3 mRNA detection in whole blood is an independent prognostic marker in mCRPC patients receiving AA‐P treatment. Furthermore, the levels of circulating KLK3 mRNA in patients receiving AA‐P treatment might reflect treatment response or early signs of progression.

Population-Based Study of Docetaxel or Abiraterone Effectiveness and Predictive Markers of Progression Free Survival in Metastatic Castration-Sensitive Prostate Cancer.

BackgroundBoth Docetaxel (DOC) and Abiraterone (ABI) improve the survival of men with metastatic, castration sensitive prostate cancer (mCSPC). However, the outcome among mCSPC patients is highly variable, while there is a lack of predictive markers of therapeutic benefit. Furthermore, there is limited data on the comparative real-world effectiveness of adding DOC or ABI to androgen deprivation therapy (ADT).MethodsWe conducted a retrospective analysis of 121 mCSPC patients treated at Odette Cancer Centre (Toronto, ON, Canada) between Dec 2014 and Mar 2021 (DOC n = 79, ABI n = 42). The primary endpoint studied was progression free survival (PFS), defined as the interval from start of ADT to either (i) biochemical, radiological, or symptomatic progression, (ii) start of first-line systemic therapy for castration-resistant prostate cancer (CRPC), or (iii) death, whichever occurred first. To identify independent predictive factors for PFS in the entire cohort, a Cox proportional hazard model (stepwise selection) was applied. Overall survival (OS) was among secondary endpoints.ResultsAfter a median follow-up of 39.6 and 25.1 months in the DOC and ABI cohorts, respectively, 79.7% of men in the DOC and 40.5% in the ABI group experienced a progression event. PFS favored the ABI cohort (p = 0.0038, log-rank test), with 78.0% (95%CI 66.4–91.8%) of ABI versus 67.1% (57.5–78.3%) of DOC patients being free of progression at 12 months. In univariate analysis superior PFS was significantly related to older age at diagnosis of mCSPC, metachronous metastatic presentation, low-volume (CHAARTED), and low-risk (LATITUDE) disease, ≥90% PSA decrease at 3 months (PSA90), and PSA nadir ≤0.2 at 6 months. Age (HR = 0.955), PSA90 (HR = 0.462), and LATITUDE risk stratification (HR = 1.965) remained significantly associated with PFS in multivariable analysis. OS at 12 months was 98.7% (96.3–100%) and 92.7% (85.0–100%) in the DOC and ABI groups (p = 0.97), respectively.ConclusionsIn this real-world group of men undergoing treatment intensification with DOC or ABI for mCSPC, we did not find a significant difference in OS, but PFS was favoring ABI. Age at diagnosis of mCSPC, PSA90 at 3 months and LATITUDE risk classification are predictive factors of PFS in men with mCSPC.

MAP17 Expression in Colorectal Cancer Is a Prognostic Factor for Disease Recurrence and Dismal Prognosis Already in Early Stage Disease

Background: Disease recurrence in colorectal cancer constitutes a major cause of significant cancer-associated morbidity and mortality. MAP17 is a small protein, and its overexpression in malignant tumors has been correlated with aggressive tumor phenotypes. The aim of the present study was to investigate the expression patterns of MAP17 in colorectal cancer specimens and to assess its clinical significance. Patients and Methods: Surgical specimens of 111 patients with primary resectable colorectal cancer constituted the study population. Expression of MAP17 was assessed by immunohistochemistry, and the results were correlated with clinical and survival data. Results: MAP17 was expressed in cancer cells and endothelial cells of tumor blood vessels. Expression of MAP17 more than 10% was correlated with advanced disease stage (p < 0.001), higher T classification (p = 0.007), the presence of lymph node metastasis (p < 0.001), vascular (p = 0.013) and perineural invasion (p = 0.012). Patients exhibiting MAP17 expression of more than 30% in cancer cells compared to those expressing MAP17 less than 10% demonstrated a significantly worse 3-year progression-free survival (35.2 vs. 91%, p < 0.001) and 5-year overall survival (40.8 vs. 91%, p < 0.001). Cox regression analysis confirmed MAP17 expression of more than 30% as a prognostic marker of progression free survival (HR 0.136, 95% CI = 0.056–0.329, p < 0.001) and overall survival (HR 0.144 [95% CI) = 0.049–0.419, p < 0.001) independent of other clinicopathological characteristics. Statistically significantly worse 3-year progression-free survival and 5-year overall survival was demonstrated in the subgroup analysis of patients with early stage cancer only and high expression of MAP17. Conclusions: High MAP17 expression in patients with colorectal cancer is a significant risk factor for cancer-associated morbidity and mortality already in early stage disease.

Is SUVmax a useful marker for progression-free survival in patients with metastatic GEP-NET receiving 177Lu-DOTATATE therapy?

The prognostic potential of pretreatment maximum standardized uptake volume (SUVmax) on gallium-68-DOTATATE was evaluated with positron emission tomography/computed tomography (68Ga-DOTATATE PET/CT) in 37 patients with G1/G2 gastroenteropancreatic neuroendocrine tumors (NET) who received peptide receptor radionuclide therapy (PRRT) with lutetium-177-[DOTAo,Tyr3] octreotate (177Lu-DOTATATE) after the failure of somatostatin analogues. The mean and total SUVmax were used in 68Ga-DOTATATE PET/CT before 177Lu-DOTATATE treatment to assess the progression-free survival (PFS). The responses of the patients were evaluated as partial response in 8 (32%) patients, stable disease in 12 (48%), and progressive disease in 5 (20%). The median PFS was 18 months; longer than this threshold in 14 patients (26.0 months) and shorter in 11 (8.4 months). The mean SUVmax of metastases in the liver (34.15±17.89 vs. 14.69±9.17, P=0.004) and mean SUVmax of all body metastatic lesions (33.05±14.32 vs. 15.26±4.84, P=0.001) were higher in patientswith longer PFS. The tumor grade, the origin of the tumor, Ki67 status, and previous somatostatin treatment history were not significantly different between the two PFS groups. The pre-treatment SUVmax values of 68Ga-DOTATATE PET/CT in lesions are a potential prognostic factor for PFS in well-differentiated gastroenteropancreatic neuroendocrine tumors undergoing 177Lu-DOTATATE treatment, and could be a useful parameter for the treatment selection.

Pre-Treatment Health-Related Quality of Life Parameters May Have Prognostic Impact in Elderly Patients with Mantle Cell Lymphoma. the Nordic Lymphoma Group MCL4 (LENA-BERIT) Experience

Background: Mantle cell lymphoma (MCL) is a rare, often aggressive type of B-cell lymphoma with poor survival and no cure. Cancer and cancer treatment has a negative impact on health-related quality of life (HRQOL) both during active disease and in the long term, and improvement of HRQOL may be one of the most important objectives of cancer therapy. In addition, baseline HRQOL has in other lymphoma populations been shown to be predictive of outcome. Hitherto, there are only few reports on HRQOL in MCL. The primary aim of this study was to explore HRQOL before, during and after chemotherapy in an elderly population with MCL. Secondary aims were to identify predictors for HRQOL, information that can be used for improvement in rehabilitation. Methods: The cohort consisted of patients included in the multicenter open-label phase Ib-II NLG-MCL4 trial (LENA-BERIT), designed to evaluate the addition of lenalidomide (LEN) to rituximab-bendamustine (R-B) as first-line treatment in elderly patients (&amp;gt;65 years) with MCL. The treatment with R-B stopped after six months, LEN continued for six more months. HRQOL was assessed by the EORTC QLQ-C30 questionnaire pre-treatment, and after 6, 12 and 24 months post study inclusion. For the functional scales and the global quality of life scale a higher score represents a better level of functioning. For the symtom scales and single items, a higher score corresponds to a higher level of symtoms. Patient scores were compared to scores from a reference population sample at baseline. Survival was analysed by Kaplan-Meier estimates, and cox regression multivariate analysis was used to assess survival with adjustments for prognostic factors, age, sex and more. Results: Fifty-one patients were enrolled, 1 patient was excluded based on screen failure. Median age was 71 years (range 62-84), 37 were men (73%). Stratified according to Mantle Cell Lymphoma International Prognostic Index (MIPI), 5 (10%) were low-risk, 18 (38%) intermediate and 26 (52%) high-risk. Follow-up time for living patients were 52 months, and for deceased patients 27 months. Median overall survival time were 52 months. The proportion of patients reporting HRQOL data was at baseline; 48 (96%), after 6 months; 33 (83%), after 12 months; 27 (89%), and after 24 months; 12 (75%). During the first six months of treatment, several functional scores deteriorated, and after 12 months it had stabilised at baseline level or better. The global health status (QoL) improved at 12 months after diagnosis, but then dropped to baseline levels after 2 years. Before treatment, patients exhibited levels of the symptom scores, comparable to the reference population. Six months after start of therapy, the scores for pain, dyspnoea and insomnia were improved, while appetite loss and diarrhoea were impaired. After 12 months, the symptom scales improved to a level superior compared both to baseline and the reference population. The population was divided into two groups, with the median as cut-off values. In the multivariate analysis, including MIPI, gender and the presence of TP53 mutation, impaired pre-treatment physical function, role function and elevated pain score were independent prognostic markers for overall survival. Role function and pain were also independent prognostic markers for progression free survival. Conclusion: In this population of elderly patients with MCL, pre-treatment HRQOL was similar to the reference population. During treatment, HRQOL deteriorated, but reverted to the same level as the reference population after treatment. Pre-treatment physical and role function and pain were independent factors associated with overall survival. These novel findings may be used to design support during treatment and improve rehabilitation. Figure Disclosures Jerkeman: Roche: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Gilead: Research Funding; Abbvie: Research Funding.

Asphericity of Somatostatin Receptor Expression in Neuroendocrine Tumors: An Innovative Predictor of Outcome in Everolimus Treatment?

Background: in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NET), the mTOR inhibitor everolimus is associated with significant improvement in progression-free survival (PFS). This study evaluated the lesional asphericity (ASP) in pretherapeutic somatostatin receptor (SSR) imaging as the first imaging-based prognostic marker for PFS. Methods: this retrospective bicentric cohort study included 30 patients (f = 13, median age, 66.5 (48–81) years) with pretherapeutic [111In-DTPA0]octreotide scintigraphy (Octreoscan®). ASP of functional volumes of up to three leading lesions per patient (n = 74) was calculated after semiautomatic, background-adapted segmentation. Uni- and multivariable Cox regression regarding PFS for clinical factors and the maximum ASP per patient was obtained. Results: all 30 patients showed metachronous or progressive liver metastases. ASP, primary tumor site, metastases pattern, and prior peptide receptor radionuclide therapy (PRRT) were significantly associated with PFS in univariable Cox regression. Only ASP > 12.9% (hazard ratio (HR), 3.33; p = 0.024) and prior PRRT (HR, 0.35; p = 0.043) remained significant in multivariable Cox. Median PFS was 6.7 months for ASP > 12.9% (95% confidence interval (CI), 2.1–11.4 months) versus 14.4 (12.5–16.3) months for ASP ≤ 12.9% (log-rank, p = 0.028). Conclusion: pretherapeutic ASP of SSR positive lesions independently predicted PFS for treatment with everolimus in GEP-NET. ASP may supplement risk-benefit assessment before patient inclusion to treatment.

Abstract A053: Significance of Transglutaminase 2 expression on clinical outcome in metastatic renal cell carcinoma

Abstract Background: A few recent studies have demonstrated a possible role of transglutaminase 2 (TG2) in tumorigenesis or progression of renal cell carcinoma (RCC). The aim of this study was to examine TG2 expression and its clinical significance in patients with metastatic clear cell RCCs (ccRCCs). Methods: We analyzed 206 metastatic ccRCC patients who received the first-line vascular endothelial growth factor (VEGF) targeted therapy including sunitinib (n = 33), pazopanib (n = 120), and sorafenib (n = 53) between 2006 and 2016. The expression of TG2 was determined by immunohistochemistry and categorized into four groups, according to membranous staining intensity: negative (0), mild (1+), moderate (2+), and strong (3+). Results: TG2 staining intensity was negative in 20.9% of ccRCC (n = 43), 1+ in 46.6% (n = 96), 2+ in 9.71% (n = 20), and 3+ in 22.8% (n = 47). The survival analysis showed a significant association between stronger TG2 expression (≥ 2+) and worse progression-free survival (PFS) (P = 0.032) in the 1st line VEGF-targeted therapy. On multivariate analysis including previous nephrectomy, number of metastatic organs, and International Metastatic RCC Database Consortium Risk Score, stronger TG2 expression was a significant independent predictive indicator for poor PFS (P = 0.004). Conclusions: Our study is the first to demonstrate the significance of TG2 expression on clinical outcome in metastatic ccRCCs. TG2 expression was a significant negative predictive marker for PFS in 1st line VEGF-targeted therapy and targeting TG2 may be a new therapeutic approach to metastatic ccRCC. Citation Format: Seung-Hoon Beom, Sejung Park, Woo Sun Kwon, Sang Joon Shin, Soo-Youl Kim, Nam Hoon Cho, Sun Young Rha. Significance of Transglutaminase 2 expression on clinical outcome in metastatic renal cell carcinoma [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A053. doi:10.1158/1535-7163.TARG-19-A053

Expanded RAS and BRAF V600 testing as predictive biomarkers for single agent cetuximab in the randomized phase III CO.17 trial.

537 Background: KRAS/NRAS ( RAS) testing of exons 2, 3 and 4 is standard prior to anti-EGFR treatment in metastatic colorectal cancer and many consider BRAFV600 ( BRAF) mutations predictive. CO.17 was a randomized phase III trial comparing cetuximab vs best supportive care (BSC) in unselected patients (pts). Re-analysis tested only KRAS exon 2, thus the benefit of cetuximab in RAS/BRAF wild type (WT) pts is unclear. Methods: We retrospectively performed expanded RAS/BRAF testing using a highly sensitive digital PCR method (BEAMing; 1% allele frequency detection limit) on micro-dissected archival tissue from 248 CO.17 pts. Additional pts without available archival tissue, with prior Sanger sequencing or therascreen results were included in analyses if mutations were previously detected (n = 77). Overall survival (OS), progression free survival (PFS), and response rates (RR) were compared by molecular profile. Results: Of 248 sequenced pts, 139 (56%) were RAS mutant, with 112 (45%) exon 2, 11 (4%) exon 3 and 6 (2%) exon 4 KRAS mutant, and 10 (4%) NRAS mutant pts. Seven (3%) BRAF mutant, and 97 (30%) confirmed RAS/BRAF WT pts were identified. Results are summarized below. A test of interaction indicated RAS status was predictive for PFS (p = 0.0001) and OS (p = 0.037) and BRAF status neared significance as a predictive marker for PFS (p = 0.089) but not OS (p = 0.24). Conclusions: These updated results demonstrate an improved PFS (HR 0.25 vs 0.40 previously) and OS (HR 0.51 vs 0.55 previously) for cetuximab in RAS/BRAF WT pts compared to prior analyses that included only KRAS exon 2 mutation status. We provide an estimate of single agent cetuximab efficacy for future anti-EGFR re-challenge studies and demonstrate further support that BRAF mutations may predict lack of benefit from anti-EGFR therapy. Clinical trial information: NCT00079066. [Table: see text]

Abstract A017: Immunologic efficacy of heat shock protein 105 peptide vaccine in patients with advanced colorectal and esophageal cancer

Abstract Purpose: Heat shock protein 105 (HSP105) is overexpressed in a variety of human cancers, including colorectal cancer (CRC) and esophageal cancer (EC). We identified HLA-A24 or A2-restricted HSP105 peptides that can induce HSP105 peptide-specific cytotoxic T lymphocytes (CTLs) (EP1536006, JP5112615, JP5291641, US9,404,925) and curried out a phase I clinical trial of HLA-A24 or A2-restricted HSP105 peptide vaccine in patients with CRC or EC (UMIN ID000017809). In this study, we aimed to demonstrate the immunological efficacy of the novel vaccine. Experimental design: 30 patients (HLA-A24 group; 15 patients, HLA-A2 group; 15 patients) with advanced CRC or EC were enrolled. Two types of vaccine (A24-1 and A24-7 or A2-7 and A2-12) were administered into the patients, matching HLA-types. Immunological responses were analyzed by ex vivo and in vitro IFN-γ ELISPOT assay using peripheral blood mononuclear cells before and after vaccination, and cytokines produced by HSP105-specific CTLs were measured by Cytometric Bead Array assay. We also analyzed the correlation between immunological responses and prognosis. Result: HSP105 peptide vaccines induced HSP105 peptide-specific CTLs in 15 of 30 patients. In HLA-A24 group, there were 7 patients with the induction only in ex vivo and almost all patients (n=13) showed skin reactions of vaccine sites. By contrast, in HLA-A2 group, there were 4 patients with the induction in ex vivo and 6 patients in in vitro, respectively, and only 6 patients with skin reactions of vaccine sites. In all patients, the existence of skin reaction correlated with the induction in ex vivo (p&amp;lt;0.01). The progression-free survival (PFS) and overall survival (OS) were significantly longer in patients with the induction (n=15) than in those without (n=15) (P&amp;lt;0.01, respectively). The peptide-specific CTL frequency correlated with OS and could be a predictive marker of PFS and OS. Furthermore, HSP105 peptide-specific cytokine production was observed in various tissues of 8 patients, such as vaccine injected sites skins, metastatic and primary tumors. It suggested that HSP105-specific CTLs not only accumulated at injected sites but also infiltrated into tumor tissues. Additionally, we succeeded in establishing two types of highly functional HSP105 peptide-specific CTL clones and sequenced the T-cell receptors (TCRs) of these clones. Conclusion: Our results suggested that HSP105 peptide vaccine could improve the prognosis of patients with advanced CRC and EC by inducing the antitumor immune responses. To further extend the efficacy, we are developing TCR-engineered T-cell therapy using TCR sequences obtained from HSP105 peptide-specific CTL clones and intratumoral injection method of this vaccine. Citation Format: Yasuhiro Shimizu, Toshiaki Yoshikawa, Kojima Takashi, Kayoko Shoda, Kazuto Nosaka, Shoichi Mizuno, Satoshi Wada, Yuki Fujimoto, Tetsuro Sasada, Kenichi Kohashi, Hideaki Bando, Itaru Endo, Tetsuya Nakatsura. Immunologic efficacy of heat shock protein 105 peptide vaccine in patients with advanced colorectal and esophageal cancer [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A017.

Predicting Overall Survival and Progression-Free Survival Using Tumor Dynamics in Advanced Breast Cancer Patients.

Prediction of survival endpoints, e.g., overall survival (OS) and progression-free survival (PFS), based on early observations, i.e., tumor size, may facilitate early decision making in oncology drug development. In this paper, using data from six randomized trials for first- or second-line advanced breast cancer (ABC) treatments with various mechanisms of action, tumor size change from baseline at different observation time points was evaluated as a predictor for survival endpoints using different modeling approaches. The aim is to establish a predictive model where tumor size change from baseline can be used as a treatment independent predictive marker for PFS and OS in first- and second-line ABC. The results showed that tumor size change at single time point (TSP) or up to certain time points as a time-varying covariate (TSTVC) were significant predictors for OS and PFS in the survival models along with other covariates identified for each line of treatment. TSP and TSTVC models performed similarly for first-line treatments; TSTVC performed significantly better for second-line treatments. Eight weeks was selected as the recommended early evaluation time of tumor size change to predict OS and PFS in both first- and second-line treatment, while better prediction can be achieved for first-line OS by using 16weeks tumor size change. The result of this study is treatment independent and can be used to predict the outcome of the clinical trials using early readout of tumor size change for the classes of drugs that have been evaluated in this study.

Evaluation of the MDACC clinical classification system for pancreatic cancer patients in an European multicenter cohort

BackgroundThe MDACC group recommends to extend the current borderline classification for pancreatic cancer into three groups: type A patients with resectable/borderline tumor anatomy, type B with resectable/borderline resectable tumor anatomy and clinical findings suspicious for extrapancreatic disease and type C with borderline resectable and marginal performance status/severe pre-existing comorbidity profile or age>80. This study intents to evaluate the proposed borderline classification system in a multicenter patient cohort without neoadjuvant treatment. MethodsEvaluation was based on a multicenter database of pancreatic cancer patients undergoing surgery from 2005 to 2016 (n = 1020). Complications were classified based on the Clavien-Dindo classification. χ2-test, Kaplan–Meier estimator and Cox regression hazard model were used for statistical analysis. ResultsMost patients (55.1%) were assigned as type A patients, followed by type C (35.8%) and type B patients (9.1%). Neither the complication rate, nor the mortality rate revealed a correlation to any subgroup. Type B patients had a significant worse progression free (p < 0.001) and overall survival (p = 0.005). Type B classification was identified as an independent prognostic marker for progression free survival (p = 0.005, HR 1.47). ConclusionThe evaluation of the proposed classification in a cohort without neoadjuvant treatment did not justify an additional medical borderline subgroup. A new subgroup based on prognostic borderline patients might be the main target group for neoadjuvant protocols in future.

Abstract 5575: A multiplexed RE-qPCR cell-free DNA assay to assess response and resistance to cancer therapy

Abstract A qPCR multiplex that utilizes two types of multi-copy retrotransposable elements (RE) in the human genome, as target loci, has been developed and validated. The single-well, qPCR reaction amplifies 80bp, 265bp and an internal-positive-control simultaneously, within 2 hours and with high PCR efficiencies. The selected RE targets comprise over 1500 copies in the genome and allow robust detection of low level cell-free (cf) DNA pg/µL) from &amp;lt;0.5mL plasma. The 80bp target measures total cfDNA. The 265bp target is used to assess cfDNA fragmentation and is presented as the DNA Integrity Index (DII=265/80) which is a ratio of the 265bp quantity divided by 80bp quantity. cfDNA concentration and integrity assessment has shown great promise as a highly sensitive, minimally invasive blood biomarker for multiple cancer types. InnoGenomics has developed an accurate, extremely sensitive liquid biopsy blood test for improved management of cancer patient care. Utilizing standard qPCR platforms for rapid and cost-effective processing, this test can reliably obtain results from small blood volumes (&amp;lt;0.5 mL of plasma), and possesses exceptionally high analytical sensitivity with a detection capability of &amp;lt; 0.1 pg of DNA (LOD). The developed assay demonstrated high predictive capacity in discriminating a group of 39 CRC stage IV patients from 40 healthy controls using cfDNA concentration and DNA Integrity Index (DII-265/80) values. All markers displayed high Area Under the receiver operating characteristic Curve (AUC) values - 80bp target: 0.9891, 265bp target: 0.9859, and DII-265/80: 0.8603. The DNA integrity ratio (DII) showed great potential as a prognostic marker for progression free survival (P=0.019). A retrospective cohort study of 3 patients demonstrated the potential use of this RE-qPCR cfDNA assay for cancer treatment monitoring. NCI SBIR Phase I studies showed high predictive capacity in discriminating metastatic colorectal cancer (CRC) patients from non-cancer healthy controls, with a significant increase in sensitivity and specificity compared to the CEA test, a serum biomarker currently used for CRC patient monitoring. Retrospective patient case studies demonstrated the test's ability to detect resistance to therapy and disease progression more accurately than CEA results and earlier than CT imaging. These results suggest strong potential clinical utility in several applications: (1) treatment monitoring for CRC stage IV patients, (2) recurrence surveillance for CRC stage I-III patients, (3) assessment of residual disease and (4) as a prognostic tool to help predict CRC patient outcomes which can serve as a tool to guide personalized/effective treatment regimens. A detailed prospective study will be undertaken during Phase II research, in collaboration with MD Anderson Cancer Center, to clinically validate the test. ACKNOWLEDGEMENT: This project was funded by an SBIR Phase I contract from NCI. Citation Format: Sudhir K. Sinha, Hiromi Brown, Zhide Fang, Mathilde Couetoux, Karen Gambaro, Gerald Batist. A multiplexed RE-qPCR cell-free DNA assay to assess response and resistance to cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5575.

Real world data on young patients with high-risk diffuse large B-cell lymphoma treated with R-CHOP or R-CHOEP - MYC, BCL2 and BCL6 as prognostic biomarkers.

BackgroundDouble expression of MYC and BCL2 proteins (DE) and double-hit MYC+BCL2/BCL6 translocations (DH) were established as important biomarkers in patients with diffuse large B-cell lymphoma (DLBCL) by the 2016 revision of the World Health Organization classification of lymphoid neoplasms. Whether this applies to the subgroup of young patients with high risk DLBCL is not known. We previously found that in a uniform retrospective population-based cohort of patients aged 18–60 years with high-risk DLBCL, the addition of etoposide to R-CHOP chemotherapy (R-CHOEP) resulted in improved survival mainly in patients with germinal center B-cell like (GCB) immunophenotype. The aim of this study was to investigate the prognostic and predictive value of DE and DH in this patient cohort.MethodsData on all young Danish patients diagnosed with de novo high-risk DLBCL 2004–2008 and treated with R-CHOP or R-CHOEP were obtained from the Danish Lymphoma database (n = 159). Tumor samples were available from 103 patients. MYC and BCL2 proteins were analyzed with quantitative immunohistochemistry (IHC) using different cut off values. MYC-, BCL2- and BCL6-translocations were examined with fluorescent in situ hybridization (FISH).ResultsDE with MYC>75% and BCL2>85% was an independent negative prognostic marker of progression free survival (PFS) in patients treated with R-CHOP but not R-CHOEP (p<0.001), also after exclusion of patients with DH. A predictive effect of DE for response (PFS) to R-CHOEP vs. R-CHOP was almost significant (p = 0.07). DH was not prognostic in this patient cohort.ConclusionIn young patients with high-risk DLBCL, treatment with R-CHOEP may overcome the negative prognostic impact of DE observed in patients treated with R-CHOP.

Sunitinib-induced hypothyroidism predicts progression-free survival in metastatic renal cell carcinoma patients

Sunitinib is a tyrosine kinase inhibitor (TKI) used in treatment of metastatic renal cell carcinoma (mRCC), gastrointestinal stromal tumors and pancreatic neuroendocrine tumors. One of the most common side effects related to sunitinib is hypothyroidism. Recent trials suggest correlation between the incidence of hypothyroidism and treatment outcome in patients treated with TKI. This study evaluates whether development of hypothyroidism is a predictive marker of progression-free survival (PFS) in patients with mRCC treated with sunitinib. Twenty-seven patients diagnosed with clear cell mRCC, after nephrectomy and in ‘good’ or ‘intermediate’ MSKCC risk prognostic group, were included in the study. All patients received sunitinib as a first-line treatment on a standard schedule (initial dose 50 mg/day, 4 weeks on, 2 weeks off). The thyroid-stimulating hormone serum levels were obtained at the baseline and every 12 weeks of treatment. In statistic analyses, we used Kaplan–Meier method for assessment of progression-free survival; for comparison of survival, we used log-rank test. In our study, the incidence of hypothyroidism was 44%. The patients who had developed hypothyroidism had better median PFS to patients with normal thyroid function 28,3 months [95% (CI) 20.4–36.2 months] versus 9.8 months (6.4–13.1 months). In survival analysis, we perceive that thyroid dysfunction is a predictive factor of a progression-free survival (PFS). In the unified group of patients, the development of hypothyroidism during treatment with sunitinib is a positive marker for PFS. During that treatment, thyroid function should be evaluated regularly.

Abstract A009: IgG4: a new tool to predict the risk of disease progression in melanoma

Abstract Purpose: Novel findings point to a pathological and immunoregulatory function of IgG4 antibodies and IgG4+ B cells in inflammatory diseases and malignancies. It has been reported that IgG4 antibodies impair humoral responses and restrict activation of immune effector cells in melanoma and cholangiocarcinomas. Thus the biological function of IgG4 may also be accompanied with predictive potential. Experimental Design: We investigated IgG4 as a potential indicator of the risk of disease progression in human sera (n=271: 167 melanoma patients; 104 healthy volunteers) and peripheral blood B cells (n=71: 47 melanoma patients; 24 healthy volunteers). Results: The serum levels of IgG4 (IgG4/IgGtotal) were elevated in melanoma samples and high IgG4 levels correlated negatively with progression-free survival (hazard ratio (HR) 2.01, 95% confidence interval ([CI]) 1.34-3.35; P=0.0016) and overall survival (HR 1.90 95%[CI] 1.17-3.29; P=0.0116). IgG4 was an independently negative prognostic marker for progression-free survival (PFS; HR 2.46, 95%[CI] 1.01-6.02) in patients with stage I-II disease. Moreover in a similar cohort elevation of IgG4+ circulating B cells (CD45+CD22+CD19+CD3-CD14-) (P=0.014) was also negatively prognostic for progression-free survival. The marker LDH, which is already used in clinical practice, is associated with PFS in melanoma, especially in advanced stages. We found that by combining LDH and IgG4 the prognostic value was improved (AUC:0.67; P=0.0002) than either serum indicator alone. In tissues (n=256; 108 cutaneous melanomas; 56 involved lymph nodes; 60 distant metastases; 32 normal skin samples) we found IgG4+ cell infiltrates in 42.6% of melanomas, 21.4% of involved lymph nodes and 30% of metastases. These findings suggest biological involvement of IgG4 in Th2 tumour environments at the metastatic and local levels. Conclusion: Our data are consistent with emerging evidence for immunosuppressive roles for IgG4, further supporting prognostic utility in melanoma and potential to facilitate patient stratification. Citation Format: Panagiotis Karagiannis, Federica Villanova, Debra H. Josephs, Isabel Correa, Mieke Van Hemelrijck, Carl Hobbs, Louise Saul, Isioma U. Egbuniwe, Isabella Tosi, Kristina M. Ilieva, Emma Kent, Eduardo Calonje, Mark Harries, Ian Fentiman, Joyce Taylor-Papadimitriou, Joy Burchel, James F. Spicer, Katie E. Lacy, Frank O. Nestle, Sophia N. Karagiannis. IgG4: a new tool to predict the risk of disease progression in melanoma. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A009.

Is CA19-9 response following induction and consolidation therapy in locally advanced pancreatic cancer (LAPC) an early surrogate marker for eventual survival outcomes?

e15230 Background: Early surrogate markers of progression-free survival (PFS) and overall survival (OS) in LAPC patients who receive consolidative chemoradiation therapy (CRT) following induction c...