Residual Disease In Patients Research Articles

Application of Cu-64 NODAGA-PSMA PET in Prostate Cancer.

The high diagnostic potential of 64Cu-PSMA PET-CT imaging was clinically investigated in prostate cancer patients with recurrent disease and in the primary staging of selected patients with advanced local disease. The aim of our study is to assess the uptake behavior in the clinical setting of 64Copper Prostate-Specific Membrane Antigen (64Cu PSMA) Positron Emission Tomography/Computed Tomography (PET/CT) in prostate cancer. A retrospective study was performed in 23 patients with intermediate, high risk and progressive disease at primary staging of prostate cancer. All patients underwent 64Cu-PSMA PET. Overall, 250MBq (4MBq per kg bodyweight, range 230-290MBq) of 64Cu-NODAGA PSMA was intravenously applied. PET images were performed 30min (pelvis and abdomen) and 1-2h post-injection (skull base to mid-thigh). Maximum standardized uptake values (SUVmax) were measured in the organs with high physiological uptake such as liver and kidney, and, additionally, background activity was measured in the gluteal area and in suspected tumor lesions using a HERMES workstation. PSMA uptake was detected in prostate bed in nine patients, in six patients in distant metastases (bone, lung and liver) and in nine patients in lymph nodes. Of 23 patients, 5 (20.8%) did not show any focal pathological uptake in the whole body. The number of sites (prostate bed, lymph nodes, distant metastases) with positive PSMA uptake was significantly associated with PSA values before imaging (P=0.0032). The 64Cu PSMA uptake increased significantly from 30min to 1-3h post-injection (Wilcoxon signed rank test, P = 0.002). 64Cu NODAGA-PSMA PET is a promising imaging tool in the detection of residual disease in patients with recurrent or primary progressive prostate cancer. Furthermore, the increased tracer uptake over time indicates in vivo stability of the diagnostic radiopharmaceutical.

Abnormal Heavy/Light Chain Ratio and Matched Pair Suppression Increase Residual Disease Detection Sensitivity in Patients With Multiple Myeloma With Deep Responses

BackgroundHeavy/light chain (HLC) assay can quantify involved as well as uninvolved immunoglobulin pairs and is used to detect monoclonal proteins. Patients and MethodsWe compared the sensitivity between HLC assay and serum protein electrophoresis, serum immunofixation electrophoresis (IFE), and free light chain (FLC) assay in patients with symptomatic multiple myeloma (n = 111) whose responses were stable disease or better. ResultsAmong patients with negative IFE and normal FLC ratios, 84.4% (38 of 45) and 80% (36 of 45) exhibited normal HLC ratios and no pair suppression, respectively (13.3% [6 of 45], moderate pair suppression and 6.7% [3 of 45], severe pair suppression). The lower the monoclonal protein levels, the more the possibility that the patients had normal HLC ratios and no matched pair suppression (both P < .000001). HLC ratios or pair suppression combined with IFE results and FLC ratios were more sensitive for detecting monoclonal proteins than were IFE results and FLC ratios alone (P = .016 and .0039, respectively). A combination of all 4 methods (IFE, FLC, HLC, and pair suppression) was far more sensitive than were IFE findings plus FLC ratios alone (P = .00024). ConclusionAbnormal HLC ratios and HLC-matched pair suppression can increase the sensitivity for detecting residual disease in patients with multiple myeloma with deep responses.

Abstract P2-10-08: A predictive test for neoadjuvant chemotherapy in breast cancer identifies a subset of triple negative patients with resistant disease and the poorest prognosis

Abstract Prediction of pathological complete response (pCR) for neoadjuvant treatment is an area of unmet clinical need, especially for triple negative breast cancer (TNBC) as pCR is correlated with better outcomes. Predicting which patients will have residual disease (RD) provides an opportunity to improve treatment planning. We developed a test to predict which patients are likely to achieve pCR or RD to the standard of care (taxane-based) neoadjuvant chemotherapy using gene expression profiling of 325 previously identified novel biomarkers. Three microarray datasets were used (GSE22226, GSE25055, and GSE25065) including a total of 594 stage II-III breast cancer patients of which 125 (21%) achieved pCR, and 469 (79%) RD. ER+ tumors were present in 57% of the patients and 52% were PGR+. Almost 90% of the patients were Her2-. Of 231 TNBC, 78 (33.8%) achieved pCR, while 153 (66.2%) RD. Of 303 ER+Her- patients 26 (8.6%) achieved pCR while 277 (91.4%) RD. The cohort was divided into balanced populations with 476 patients used for training (80%) and test (20%) rounds of model development, while 118 patients were reserved as a validation set. Combining a “winnowing” process to remove genes with least predictive power, and hundreds of thousands of step-wise runs, followed by ranking genes based on conditional probabilities, we developed a 17-gene cassette (BA100) which was locked-down in the validation set with ROC (AUC) = 0.818. With a cut-off of 83% sensitivity and 68% specificity (PPV 0.4; NPV 0.94), BA100 achieved a 16% true positive rate (true pCR) and 55% true negative rate (true RD) identifying 76% of the patients who achieved pCR, and 69% of the patients with RD. In TNBC, BA100 classified 29% as true positives (TP), 36% as false positive (FP), 30% true negative (TN), and 4.8% false negative (FN). Kaplan Meier (KM) curves showed a significant difference in 5-year disease-free survival (5Y DFS) between TP and TN (p=0.00453) or FP (p=2.09E-06). However, FP had even worse outcomes than TN patients. To improve the TP rate, additional genes expressed in TNBC plus the original 325 genes were subjected to a second round of gene selection to discriminate between TP and FP, resulting in a 16-gene cassette (BA100.1). With a cut-off of 95% sensitivity and 73% specificity (PPV 0.7; NPV 0.95), applying BA100.1 reduced the FP rates from 24% to 9%, while correctly identifying 88% of RD in the validation set. KM curves showed no significant difference in 5Y DFS between 124 TNBC (53.7%) classified as TN versus 29 TNBC (12.6%) classified as FP, while a significant difference in survival rate was found between TNBC classified as TN vs TP (Cox Proportional Harzard p=8.42e-05). Taken together, we developed a predictive test consisting of two gene cassettes that accurately identified 71% (88/104) of pCR, and 88% (417/469) of RD patients. Gene cassettes include several transcriptional repressors, PI3K signal transduction, components of telomerase, DNA repair genes, fatty acid metabolism and estrogen-independent proliferation. The test stratified TNBC with differential response to chemotherapy and survival rates so that novel approaches can be used without delay. Further validation will confirm the test utility. Citation Format: Fournier MV, Chen J, Obenauer J, Goodwin EC, Tannenbaum SH, Brufsky AM. A predictive test for neoadjuvant chemotherapy in breast cancer identifies a subset of triple negative patients with resistant disease and the poorest prognosis [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-10-08.

PP2A inhibition sensitizes cancer stem cells to ABL tyrosine kinase inhibitors in BCR-ABL+ human leukemia.

Overcoming drug resistance and targeting leukemic stem cells (LSCs) remain major challenges in curing BCR-ABL+ human leukemia. Using an advanced drug/proliferation screen, we have uncovered a prosurvival role for protein phosphatase 2A (PP2A) in tyrosine kinase inhibitor (TKI)-insensitive leukemic cells, regulated by an Abelson helper integration site-1-mediated PP2A-β-catenin-BCR-ABL-JAK2 protein complex. Genetic and pharmacological inhibition of PP2A impairs survival of TKI nonresponder cells and sensitizes them to TKIs in vitro, inducing a dramatic loss of several key proteins, including β-catenin. We also demonstrate that the clinically validated PP2A inhibitors LB100 and LB102, in combination with TKIs, selectively eliminate treatment-naïve TKI-insensitive stem and progenitor cells, while sparing healthy counterparts. In addition, PP2A inhibitors and TKIs act synergistically to inhibit the growth of TKI-insensitive cells, as assessed by combination index analysis. The combination eliminates infiltrated BCR-ABL+ blast cells and drug-insensitive LSCs and confers a survival advantage in preclinical xenotransplant models. Thus, dual PP2A and BCR-ABL inhibition may be a valuable therapeutic strategy to synergistically target drug-insensitive LSCs that maintain minimal residual disease in patients.

Efficacy of surgery and imatinib mesylate in the treatment of advanced gastrointestinal stromal tumor: a systematic review.

In patients with localized gastrointestinal stromal tumors, surgery remains the elective treatment. Nowadays, imatinib therapy has been standardized in advanced gastrointestinal stromal tumors, showing continuous improvements in progression-free and overall survival. A combination of imatinib therapy and surgery may also be effective in a subset of patients with metastatic or unresectable gastrointestinal stromal tumors. In this review, the authors analyzed the role of imatinib mesylate associated to surgery in unresectable and/or metastatic gastrointestinal stromal tumors. We searched for all published and unpublished randomized controlled clinical trials and controlled clinical trials. We conducted the review according to the recommendations of The Cochrane Collaboration. We used Review Manager 5 software for the statistical analysis. There are currently no randomized controlled clinical trials or controlled clinical trials on this issue. We performed a subgroup analysis in the patients preoperatively treated with imatinib mesylate. This subgroup revealed a minor incidence of recurrent or metastatic gastrointestinal stromal tumors and a greater incidence of locally unresectable gastrointestinal stromal tumors in the responsive disease group (P = 0.001). In this patient group, more complete resections were observed (P = 0.00001). Furthermore, in the same patient group we observed a more significant 12 and 24-month disease-free survival after imatinib treatment and complete resection (respectively P= 0.06 and P= 0.003) and also a better 24-month overall survival (P = 0.004). There is actually only one ongoing European randomized study evaluating surgery of residual disease in patients with metastatic gastrointestinal stromal tumors responding to imatinib mesylate. Imatinib mesylate represents the standard treatment as preoperative supplement for locally unresectable and/or metastatic gastrointestinal stromal tumors, and a trial to compare the approach versus surgery alone is not necessary. For patients responding to imatinib or patients with prolonged stable disease, resection of residual disease should be considered. A phase III randomized study evaluating surgery of residual disease in patients with metastatic gastrointestinal stromal tumor responding to imatinib mesylate, EORTC 62063, has been opened. Moreover, surgery should be considered for patients at higher risk of complications during pharmacological debulking. In advanced gastrointestinal stromal tumors, the advantages of the integrated treatment are significant in the complete or partial response disease group in terms of more complete resections and better disease-free and overall survival.

Retrospective audit of patients referred for further treatment following Mohs surgery for non-melanoma skin cancer.

To describe the characteristics, subsequent management and outcomes of patients referred for further management following Mohs micrographic surgery (MMS) for basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Retrospective analysis of patients referred to a quaternary cancer centre from 2000 to 2015. In total, 83 lesions in 82 patients were referred for further management; 52 (62%) were SCC and 80 (96%) were located in the head and neck. Reasons for referral included high-risk disease for consideration for adjuvant radiotherapy (37/83, 45%), inadequate resection (28/83, 34%) or recurrence following previous MMS (15/83, 17%). Fewer than 40% of the 69 referrals received from MMS surgeons included photos or an operative report and diagram. There was discordance in pathology opinion in 11 (13%) of cases. Histopathology from MMS was reviewed in eight cases and there was discordance with the in-hospital pathology opinion in six of these. In-hospital re-excision was performed in 19 cases and in five of these the pathology report on the paraffin-sectioned re-excised tissue was discordant with prior MMS assessment. Significantly, two cases were associated with a misinterpretation of lymphocytic infiltrate as residual disease in patients with chronic lymphocytic leukaemia (CLL). This study highlights some of the challenges and limitations of MMS. Early referral for multidisciplinary management is recommended when MMS resection margins are inadequate or uncertain, especially for high-risk SCC. We recommend that referrals be accompanied by histological material, as well as a detailed report with operative photos and diagrams. CLL can pose an intraoperative diagnostic challenge. Discrepancies in the interpretation of MMS slides present an opportunity for improvement, and our findings support the role of ongoing quality assurance programs.

The Relationship of BrafV600E Mutation Status to FDG PET/CT Avidity in Thyroid Cancer: A Review and Meta-Analysis

Papillary thyroid cancer (PTC) harboring a BRAFV600E gene mutation has been shown to exhibit aggressive tumor behavior and carries higher risks of recurrence and disease-specific death. In this systematic review and meta-analysis, we examined published evidence related to the accuracy of fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) in detection of residual disease in patients with BRAFV600E mutated thyroid cancer. We extracted data from PUBMED/MEDLINE and EMBASE published between January 1995 and March 2017. We included studies that compared FDG PET standardized uptake values (SUVs) between BRAFV600E-positive and BRAFV600E-negative subjects, as well as those that evaluated the odds of having FDG avidity between BRAFV600E-positive and -negative patients with thyroid cancer. There were a total of 12 studies in the systematic review. Seven studies qualified for the analysis for calculating the pooled odds ratio (OR). The pooled cohort with binary data had 1,144 patients out of which 843 were BRAFV600E positive and 301 were BRAFV600E negative. Those with a BRAFV600E mutation had a significantly greater likelihood of having FDG-avid lesions. The pooled OR was 2.12 (confidence interval [CI] 1.53-3.00, P<.01). The pooled mean SUV (cohort of 315 patients) was significantly higher in BRAFV600E-positive compared to BRAFV600E negative patients, with a pooled mean difference of 5.1 (CI 4.3-5.8). Our meta-analysis shows that presence of BRAFV600E mutation in PTC confers a higher likelihood of FDG PET avidity and is associated with higher SUV uptake values compared to BRAFV600E-mutation negative status. BRAF = B-Raf proto-oncogene, serine/threonine kinase; CI = confidence interval; CT = computed tomography; DTC = differentiated thyroid cancer; FDG = fluorodeoxyglucose; PET = positron emission tomography; PTC = papillary thyroid cancer; SUV = standardized uptake value.

Minimum Residual Disease in Patients Post Radical Prostatectomy for Prostate Cancer: Theoretical Considerations, Clinical Implications and Treatment Outcome

Introduction:Minimal residual disease (MRD) remaining after curative therapy for prostate cancer has the potential for growth and can result in metastasis. Circulating prostate cells (CPCs) and bone marrow micro-metastasis (mM) could represent different types of MRD. We here determined; biochemical failure free survival rates; time to BF after 10 years follow-up; and the presence of CPCs and mM in patients treated with radical prostatectomy (RP) for prostate cancer.Methods and Patients:One month after RP, blood and bone marrow were sampled for assessment of CPCs and mM. Cases were classified as: group A, CPC negative and mM negative; group B, CPC negative and mM positive; Group C, CPC positive and mM negative; and Group D, CPC positive and mM positive. Subjects were followed with serial determination of PSA levels, recording the time at which BF occurred defined as a serum PSA >0.2ng/ml. After ten years of follow-up Kaplan-Meier survival curves were generated and the restricted mean survival time (RMST) for each group calculated.Results:A total of 321 men participated, 140 in group A with survival of 92.7% (86.3 to 96.2), 39 in group B with 55.8% (37.2 to 70.9); 54 in group C with 6.41% (1.19 to 18.21) and 88 in group D with 4.96%(1.64 to 11.13%. The RMST (in years) were: group A, 9.47 (9.24 to 9.69); group B, 9.23 (8.87 to 9.58); group C, 4.62 (4.46 to 4.77); and group D, 3.57 (3.52 and 3.63) (p-value<0.001 between groups: A versus C and D, B versus C and D).Conclusions:CPC positive men have more aggressive disease, with increased early failure; men who are only positive for mM are at greater risk of late failure. These two forms of MRD represent different clinical entities with respect to biochemical failure and could be used to guide clinical treatment decisions.

Fighting Resilient Cancers with Iron.

Tumor progression and resistance to treatment are often accompanied by the polarization of malignant cells towards a mesenchymal or poorly differentiated state. Such a transition generates an accrued vulnerability to the induction of ferroptosis, potentially paving the way to novel therapeutic strategies for targeting residual disease in patients with cancer.

Graft-Versus-Leukemia Effect of Allogeneic Stem-Cell Transplantation and Minimal Residual Disease in Patients With Acute Myeloid Leukemia in First Complete Remission.

The detection of minimal residual disease (MRD) in patients with acute myeloid leukemia (AML) may improve future risk-adapted treatment strategies. We assessed whether MRD-positive and MRD-negative patients with AML benefit differently from the graft-versus-leukemia effect of allogeneic hematopoietic stem-cell transplantation (alloHSCT). A total of 1,511 patients were treated in subsequent Dutch-Belgian Hemato-Oncology Cooperative Group and the Swiss Group for Clinical Cancer Research AML trials, of whom 547 obtained a first complete remission, received postremission treatment (PRT), and had available flow cytometric MRD before PRT. MRD positivity was defined as more than 0.1% cells with a leukemia-associated immunophenotype within the WBC compartment. PRT consisted of alloHSCT (n = 282), conventional PRT by a third cycle of chemotherapy (n = 160), or autologous hematopoietic stem-cell transplantation (n = 105). MRD was positive in 129 patients (24%) after induction chemotherapy before proceeding to PRT. Overall survival and relapse-free survival were significantly better in patients without MRD before PRT compared with MRD-positive patients (65% ± 2% v 50% ± 5% at 4 years; P = .002; and 58% ± 3% v 38% ± 4%; P < .001, respectively), which was mainly because of a lower cumulative incidence of relapse (32% ± 2% compared with 54% ± 4%; P < .001, respectively). Multivariable analysis with adjustment for covariables showed that the incidence of relapse was significantly reduced after alloHSCT compared with chemotherapy or autologous hematopoietic stem cell transplantation (hazard ratio [HR], 0.36; P < .001), which was similarly exerted in both MRD-negative and MRD-positive patients (HR, 0.38; P < .001; and HR, 0.35; P < .001, respectively). The graft-versus-leukemia effect of alloHSCT is equally present in MRD-positive and MRD-negative patients, which advocates a personalized application of alloHSCT, taking into account the risk of relapse determined by AML risk group and MRD status, as well as the counterbalancing risk of nonrelapse mortality.

P-289 - Association of poor differentiation or positive vertical margin with residual disease in patients with subsequent colectomy after complete macroscopic endoscopic resection of early colorectal cancer

Introduction: In presence of unfavorable pathologic results after endoscopic resection of colorectal cancer, colectomy is routinely performed. We determined the risk factors for residual diseases in patients with colectomy after complete macroscopic endoscopic resection of early colorectal cancer. Methods: We identified consecutive patients who underwent endoscopic resection of early colorectal cancer and subsequently underwent colectomy, from January 2011 to December 2014. Clinicopathologic risk factors related to the residual disease were analyzed. Results: In total, 148 patients underwent endoscopic resection and subsequent colectomy. Residual disease on colectomy was noted in 16 (10.9%) patients. The rates of poorly differentiated/mucinous histology (p = 0.028), and of positive or unknown vertical resection margin (p = 0.047) were higher in patients with residual disease than in those without. In multivariate analysis, a poorly differentiated/mucinous histology and positive or unknown vertical resection margin were significantly associated with residual disease (odds ratio = 7.508 and 2.048, p = 0.015 and 0.049, respectively). Conclusion: After complete macroscopic endoscopic resection of early colorectal cancer, there is a greater need for additional colectomy in cases with a positive or unknown vertical resection margin or a poorly differentiated/mucinous histology, because of their higher risk of residual cancer and lymph node metastasis.

Detecting ultra low-frequency variants and gene fusions in lung cancer patients using an amplicon-based Firefly NGS method.

e23062 Background: The analysis of EGFR, KRAS, and BRAF mutations and Alk fusion is critical for guiding targeted therapy selection, detecting drug resistance, and monitoring residual disease in patients with NSCLC. Designing next-generation sequencing (NGS) assays for detecting low-frequency variants, however, is an ongoing challenge. The limited availability of cfDNA combined with the breadth of coverage necessary to create meaningful, clinically-actionable results requires a solution with multiplex capacity which, in turn, requires greater technological sensitivity and specificity. Here we aim to develop such a solution: an ultra-accurate NGS technology using concatmer-based error correction with amplicon workflow for fast detection of rare mutations including SNV and fusion. Methods: We developed an amplicon-based panel covering variants of EGFR, BRAF, and KRAS, as well as a panel to detect Alk fusion. CfDNA simulate and cfDNA from healthy individuals were used to test assay sensitivity and specificity. Further validation was performed via a comparative analysis of 64 late-stage lung cancer patients using both Firefly -Comet and ddPCR. Results: Analytical sensitivity of the EGFR-TKI 3-gene panel was 100% detection at an allele frequency of 0.1% for 20ng of cfDNA input. Similarly, analytical sensitivity of the Alk fusion panel was 75% detection at an allele frequency of 0.1% and 100% at an allele frequency of 0.25% for the same input. Among our patient cohort, 5 EGFR variants (19del, T790M, L858R, G719X, L861X) and 2 KRAS variant (G12X) were detected. Firefly-Comet demonstrated strong per-variant detection-rate concordance ( &gt; 99%) compared to ddPCR results. The PPV is 100% and the NPV is 98.7%. Statistical analysis of reported allele frequency concordance between Firefly-Comet and ddPCR reveals R-Sq &gt; 0.9. Conclusions: In summary, we have developed Firefly-Comet, an easy-to-use amplicon-based NGS assay capable of detecting single-digit copies of somatic mutants and gene fusions in cfDNA. The multiplex capacity of Firefly-Comet makes it well-suited for supporting targeted therapy selection, drug resistance detection, and treatment monitoring.

IFN-α Is Effective for Treatment of Minimal Residual Disease in Patients with Acute Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation: Results of a Registry Study

The efficacy of minimal residual disease (MRD)-directed IFN-α treatment was investigated in acute leukemia patients who were positive for MRD after allogeneic hematopoietic stem cell transplantation (allo-HSCT) (n = 107). MRD-positive status was defined as positivity for leukemia-associated aberrant immune phenotypes or positivity for Wilms' tumor gene 1 in a single bone marrow sample. Recombinant human IFN-α-2b injections were administered subcutaneously 2 to 3 times per week for 6 months. The 2-year cumulative incidence of severe acute and chronic graft-versus-host disease after IFN-α treatment was 5.7% and 6.6%, respectively. Eighty-one patients (75.7%) turned MRD-negative after IFN-α treatment 1 month (42; 39.3%), 2 months (6; 5.6%), 3 months (7; 6.5%), and >3 months (26; 24.3%) after MRD-directed IFN-α treatment. Twelve patients showed relapse after IFN-α treatment, and 7 died of relapse. Four patients died of nonrelapse mortality (NRM). The 2-year cumulative incidence of relapse, relapse mortality, and NRM after IFN-α treatment was 11.5%, 6.8%, and 4.3%, respectively. The 2-year probabilities of event-free survival, disease-free survival, and overall survival after IFN-α treatment were 66.5%, 82.4%, and 87.4%, respectively. Persistent MRD after IFN-α treatment was significantly associated with higher relapse risk and poorer survival. Thus, MRD-directed IFN-α treatment is effective for patients who were MRD-positive after allo-HSCT. The study was registered at http://clinicaltrials.gov as NCT02185261.

Abstract P5-16-14: NOSTRA PRELIM: A non randomised pilot study designed to assess the ability of image guided core biopsies to detect residual disease in patients with early breast cancer who have received neoadjuvant chemotherapy to inform the design of a planned trial

Abstract BACKGROUND Patients receiving neoadjuvant chemotherapy for breast cancer go on to have surgery regardless of their response. Women with HER-2 positive ER negative tumours (7.5% of all operable breast cancers in the UK) respond so well to neoadjuvant treatment with dual anti-HER2 therapy in combination with chemotherapy that pathological complete response rates of 80% can be achieved. This means that for patients receiving this treatment surgery is being performed to remove a cancer that isn't there in the large majority. A study is planned in the UK (NOSTRA ) to assess if it is feasible to treat patients with HER-2 positive ER negative breast cancer who achieve a pCR after neoadjuvant chemotherapy with trastuzmab and pertuzumab with radiotherapy alone. The first phase of the trial will be a feasibility study commencing in 2017 where all patients will have image guided tumour bed biopsies post treatment and all patients will have surgery. If the group of patients where a pCR is achieved can be accurately identified then a phase III trial randomising to surgery and radiotherapy or radiotherapy alone is planned. The NOSTRA PRELIM study reported here assessed the ability of post neoadjuvant chemotherapy tumour bed biopsies to detect residual disease to provide experience to inform the much larger NOSTRA feasibility trial biopsy protocol. METHODS 23 consecutive patients with operable primary breast cancer scheduled for neoadjuvant chemotherapy were approached to take part in the study and 20 gave consent. All 20 patients had a clip inserted into the tumour bed under ultrasound(USS) guidance at diagnosis as is standard procedure. The number of cores taken ranged from 2-6. The median number of biopsies was 4 Tumour size range at diagnosis was 15-61mm with USS. All received neo-adjuvant chemotherapy and those who were Her2 positive received neoadjuvant trastusumab. At completion all patients had USS guided tumour bed biopsy. They then went on to have surgery, after which pathology was assessed and an RCB score calculated for each patient. For this study patients all tumour types were included as non pCR outcomes were required to determine accuracy and inform changes to the biopsy protocol for future use. RESULTS Only 2 patients in this study achieved a pCR Residual disease was correctly identified in 16/20 patients. Four patients had no tumour in their post treatment biopsies but had small residual invasive tumour at surgery. The size of residual disease in these patients ranged from 0.5 -9mm and all these patients had 3 core biopsies. One patient had negative post treatment biopsies and a PCR of their invasive tumour. This patient had a diagnostic biopsy that confirmed separate area of DCIS several centimetres from the invasive component. This area did not undergo post treatment tumour bed biopsies (although both areas were clipped at diagnosis). CONCLUSION A protocol for biopsy in the upcoming NOSTRA feasibility study has been designed to both take more biopsies and sample a larger area of the tumour bed in order minimise the false negative rate. Citation Format: Francis A, Herring K, Molyneux R, Jafri M, Trivedi S, Shaaban A, Rea DW. NOSTRA PRELIM: A non randomised pilot study designed to assess the ability of image guided core biopsies to detect residual disease in patients with early breast cancer who have received neoadjuvant chemotherapy to inform the design of a planned trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-16-14.

Abstract P2-04-07: Immune profiling of post neoadjuvant high metastatic risk (RCB-II/III) residual disease in patients with early triple negative breast cancers

Abstract Background: Poor prognosis in TNBC can be predicted in the significant fraction of patients with large volume residual cancer burden (RCB-II/III) after neoadjuvant chemotherapy (NACT). Whilst residual disease has been characterised to identify “driver” mutations and copy number variations, the contribution of the immune response within its tumour microenvironment remains unclear. Here we aimed to: 1) assess the potential spatial heterogeneity of immune transcript related gene expression between areas of tumour approximately 1cm apart as might still occur with a radiologically guided biopsy through the residual disease; and 2) assess the immune stroma composition of the TNBC high metastatic risk RCB II/III disease. Method: 12 TNBC post NACT RCB II/III residual cases were identified from the KHP biobank. H&amp;E sections were reviewed and areas of tumor 1cm apart within a residual resection specimen marked as area A and area B. HistoQuest analysis software was used to quantify the proportion of tumor infiltrating lymphocytes (per total cell count) within both areas. RNA was extracted from both areas and immune gene expression profiling performed using a Nanostring nCounter® on all 24 samples. The immune PanCancer panel consisted of 770 genes combining markers for different immune cell populations. Differential genes between paired samples were compared and unsupervised hierarchical clustering using 770 genes and immune cell types performed. Results:Quantitative comparison of the tumour infiltrating lymphocytes (TILS) between area A and B revealed that 73% (8/11) of the cases had a &amp;lt;2-fold difference in the percentage of TILS within a residual specimen; and 27% (3/11) displayed a &amp;gt;2-fold (range 2.03-3.16) difference in the TILS. When comparing the 770 gene expression profiles between sampling areas in the same tumour, we found little spatial heterogeneity with areas A/B clustering together in 10 out of 12 cases. Interestingly, the two cases that revealed spatial heterogeneity within the paired samples displayed little immune cell heterogeneity histologically (i.e. &amp;lt;1-fold change in the TILS percentage score between area A and B). Comparing patient samples by immune gene expression profiling divided the patients into two groups: i) those with immunologically enriched tumors in whom gene signatures for majority of the immune cell types (DC, Macrophages, CD8+T-cells, T-helper cells (Th17, Th2, Th1), Tregs, NK, B-cells, Neutrophils, Mast cells) were highly expressed and ii) those with immunologically inert tumors in whom the immune cell signatures were not highly expressed. Within our patient cohort, patients with immunologically enriched gene expression profiles were also seen to display higher TILS score (ranging between 28.17% to 40.66%) as compared to patients with immunologically inert gene expression with scores ranging from 11.82% to 16.80%. Conclusion: The findings that high metastatic risk residual disease can be further characterized as either “immunologically inert” or “immunologically enriched” at the level of extensive immunological transcript gene expression and by histological assessment of TILS requires further investigation; and is being validated in a larger sample set. Citation Format: Irshad S, Cheang M, Gazinka P, Naidoo K, Buus R, Pinder S, Dowsett M, Tutt A. Immune profiling of post neoadjuvant high metastatic risk (RCB-II/III) residual disease in patients with early triple negative breast cancers [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-04-07.

Role of Imaging in Testicular Cancer

Testicular malignancy is the most common nonhematologic malignancy in young men. Around 95% of them are germ cell tumors (GCTs), and with correct assessment of the disease and application of chemotherapy and radiotherapy survival rates of more than 90% can be achieved. Imaging studies not only aid in the diagnosis of testicular cancer but also help determine the tumor extent and site of metastatic disease, in monitoring treatment response, surgical planning and detecting sites of relapse and residual disease. Scrotal sonography combined with clinical examination has a high sensitivity for diagnosing testicular cancer and thus is often the first imaging modality to be performed on patients presenting with testicular mass. Abdominal and pelvic CT and chest CT remain the preferred techniques for staging, monitoring of treatment response, and detecting relapse and residual disease in patients with testicular cancer but MRI, PET with 18F-FDG (fluorodeoxyglucose) and sonography also show promises in certain situations. This article reviews the literatures on the role of imaging in the management of testicular germ cell cancer. Keywords: Testicular cancer, Testicular mass, CT, MRI, Diagnosis, Staging, Imaging.

Association of post-treatment positron emission tomography with locoregional control and survival after radiation therapy for squamous cell carcinoma of the vulva

Background/purposeThe aim of this study was to investigate the use of post-treatment F-18 fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) for vulvar cancer and compare metabolic response to clinical outcomes. Materials/methodsThis retrospective study included 21 patients with vulvar squamous cell carcinoma treated with curative-intent radiation between 2007 and 2015. All patients received intensity-modulated radiation treatment (IMRT), a pre-treatment FDG/PET-CT, and a post-treatment FDG-PET/CT performed at a median time of 3months post-IMRT. ResultsMedian follow-up time was 28months. Post-treatment FDG-PET/CT demonstrated no evidence of disease (NED) in 12 patients and residual or progressive disease (PD) in 9. FDG-PET/CT response significantly correlated with biopsy-proven locoregional failure (p=0.02) and was the only significant factor associated with overall survival (OS) (p=0.049). Patients with NED on FDG-PET had a 2-year locoregional control (LRC) of 89% versus 25% for those with PD (p<0.01). Patients with NED on FDG-PET/CT had a 2-year OS of 100% versus 42% for those with PD (p=0.02). FDG-PET/CT evaluation had a sensitivity of 100% and a specificity of 71% for detecting pathologically proven residual disease in patients receiving neoadjuvant or definitive radiation. ConclusionIn this single-institution study of women with vulvar cancer, post-treatment response on FDG-PET/CT was associated with LRC and OS.

Association of Poor Differentiation or Positive Vertical Margin with Residual Disease in Patients with Subsequent Colectomy after Complete Macroscopic Endoscopic Resection of Early Colorectal Cancer.

In the presence of unfavorable pathologic results after endoscopic resection of colorectal cancer, colectomy is routinely performed. We determined the risk factors for residual diseases in patients with colectomy after complete macroscopic endoscopic resection of early colorectal cancer. We identified consecutive patients who underwent endoscopic resection of early colorectal cancer and subsequently underwent colectomy, from January 2011 to December 2014. Clinicopathologic risk factors related to the residual disease were analyzed. In total, 148 patients underwent endoscopic resection and subsequent colectomy. Residual disease on colectomy was noted in 16 (10.9%) patients. The rates of poorly differentiated/mucinous histology (p = 0.028) and of positive or unknown vertical resection margin (p = 0.047) were higher in patients with residual disease than in those without. In multivariate analysis, a poorly differentiated/mucinous histology and positive or unknown vertical resection margin were significantly associated with residual disease (odds ratio = 7.508 and 2.048, p = 0.015 and 0.049, resp.). After complete macroscopic endoscopic resection of early colorectal cancer, there is a greater need for additional colectomy in cases with a positive or unknown vertical resection margin or a poorly differentiated/mucinous histology, because of their higher risk of residual cancer and lymph node metastasis.

Minimal Residual Disease in Patients with Follicular Lymphoma Treated with Obinutuzumab or Rituximab As First-Line Induction Immunochemotherapy and Maintenance in the Phase 3 GALLIUM Study

Minimal Residual Disease in Patients with Follicular Lymphoma Treated with Obinutuzumab or Rituximab As First-Line Induction Immunochemotherapy and Maintenance in the Phase 3 GALLIUM Study

Interim Analysis of Lenalidomide Consolidation on Minimal Residual Disease in Patients with Chronic Lymphocytic Leukemia Following Initial FCR Chemotherapy - CLL6 Residuum Study of the Australian Leukaemia and Lymphoma Group (ALLG) and the French Innovative Leukemia Organization (FILO)

IntroductionPatients with residual disease following initial treatment of chronic lymphocyticleukemia(CLL) withfludarabine, cyclophosphamide and rituximab (FCR) chemotherapy have reduced progression free (PFS) and overall survival (OS). The CLL6 RESIDUUM trial is a joint trial of the Australasian Leukaemia and Lymphoma Group (ALLG) and the French CLL branch of the French InnovativeLeukemiaOrganization (FILO) thatanalyzesthe role oflenalidomide(LEN) as consolidation therapy in patients following front-line treatment for CLL who do not enter minimal residual disease (MRD) negative complete remission.MethodsCLL patients with CIRS score <6 requiring treatment according to iwCLLcriteria receive 6 cycles of FCR. Following completion of treatment, those with clinical, radiological and/or multiparameterflow cytometry (MFC) evidence of residual CLL in blood or bone marrow are randomized 1:1 to receive 2 years of maintenance treatment with LEN 10 mg daily or observation (OBS). Patients are reviewed for evidence of clinical progression, and peripheral blood and bone marrow are sampled regularly for evidence of MRD. CT scans are performed until resolution of lymphadenopathy and splenomegaly. Flow analysis for MRD is performed at two central laboratories using ERIC accredited methodology to achieve a sensitivity of 10-4. The primary end point of the study is time to progression or death.ResultsAs of end of July 2016, data from 79 patients randomized on the study were analyzedfor the effects of consolidation treatment on blood and marrow MRD. Median duration from randomization was 488 days. There were 63 males and 16 females. Median age was 62 years (range 29 to 81). 37 patients were randomized to receive LEN, 42 to OBS .On the LEN arm 13, 3 and 21 patientsvs 12, 9 and 21 on the OBS arm were in CR, nodular PR and PR respectively at the time of randomization. There were 26 serious adverse events (SAEs) reported in 22 patients. 12 SAEs in 11 patients were attributed to LEN including pneumonia/chest infection (n=4), pulmonary infiltrate (1), prostatitis (1) second primary malignancy (SPM) (1), vomiting (1), neutropenia (1), tumorflare (1), acute kidney injury (1) and anal warts (1). There were 5 SAEs in the OBS arm comprising SPM (2), neutropenia (1), gout (1) and GuillainBarre syndrome(1). Peripheral blood samples were analyzedprior to consolidation and at 3, 6 and 12 months and every 6 months thereafter. MRD levels during consolidation were compared with pre-consolidation levels and categorized as increasing, decreasing, stable detectable or stable undetectable (Fig 1). MRD increased over the period of observation in 38% of patient on the LEN arm and in 62% of patients on the OBS arm (p = 0.032, Χ2). 10 patients (27%) in the LEN arm and 2 patients (5%) in the control arm had decreasing levels of MRD in the blood (p = 0.006, Χ2). There was no difference between consolidation treatments in the percentage of patients with stable blood MRD measurements, whether in the detectable or the undetectable range. The effect of LEN was most apparent in patients in PR at randomization where 5 patients (24%) taking LEN had increasing MRD in the blood compared to 15 patients (71%) on the OBS arm (p = 0.002, Χ2). Bone marrow MRD levels were assessed prior to consolidation and after 12 months in 9 patients in each arm of the study (LEN arm 2 CR, 1 nPR, 6 PR; OBS arm 4 CR, 1 nPR, 4 PR at randomization). Eight patients in the LEN arm and 2 patients in the OBS arm were observed to have a reduction in marrow MRD. There was a significant reduction between the 2 time points in the LEN arm (p=0.022 paired Wilcoxon test) but not in the OBS arm. Four of 9 patients in the LEN arm and 1 patient in the OBS arm achieved marrow MRD values below 10-4 after 1 year on trial.ConclusionLEN consolidation therapy for residual disease after FCR front-line therapy for CLL is associated with improved control of MRD in both blood and bone marrow. A large group of recently randomized patients will provide more data to determine whether these encouraging results will translate into improved progression free and overall survival. [Display omitted] DisclosuresGottlieb:Indee: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees. Aurran:Janssen: Honoraria. Tam:Gilead: Honoraria; Roche: Honoraria; Abbvie: Honoraria; Janssen: Honoraria. Letestu:Roche: Honoraria; Alexion: Honoraria. Levy:Roche: Honoraria; Gilead: Honoraria; Abbive: Honoraria; Janssen: Honoraria. Leblond:Roche: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Abbvie: Honoraria. Mulligan:GSK: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau. Cymbalista:Abbvie: Honoraria; Roche: Honoraria; Janssen: Consultancy, Research Funding; Gilead: Consultancy, Honoraria.