Lymph Node Mets Research Articles

Cutaneous metastasis in a case of carcinoma floor of mouth- A rare case report

The incidence of cutaneous metastasis in head and neck cancers is less than 1%. Carcinoma of the oral cavity is one of the most common cancers of the head neck region with frequent metastasis to internal organs, especially the lungs, liver, and bone.We present a case of Carcinoma of floor of mouth with cutaneous metastasis.A 55 year old lady presented to our department with complaints of non-healing ulcer in the oral cavity and ulcerated nodules over neck and chest. On examination, mouth opening tongue mobility was restricted with grade 2 trismus. An ulcer in left gb sulcus, bilateral lymphadenopathy and multiple ulcerated skin nodules on neck and chest wall were noted. CECT Face and Neck showed heterogenously ehancing mass at the floor of mouth involving left buccal mucosa and erosion of mandible, lymph node mets and skin nodules. ECOGPS was 1.She was treated with palliative systemic chemotherapy and thereafter Palliative radiation. Now she is having stable disease and is on metronomic chemotherapy with regular follow up.Our case has highlighted that cutaneous metastasis can be seen in the cancers of floor of mouth. Palliative chemotherapy and radiotherapy can significantly increase Progression free survival and hence the Quality of life of patients with such presentation.

Abstract 2762: Spatial distribution and immune cell infiltration at different sites of melanoma metastases (mets)

Abstract Purpose: The site of metastasis in advanced melanoma patients (pts) influences pt response to immunotherapy and overall prognosis. Liver mets are particularly resistant to immunotherapy and their presence often confers shorter survival and reduced response rates. This study characterised and compared the tumor immune microenvironment of melanoma mets at different anatomical sites. Methods: T-cell and myeloid cell markers were stained using multiplex IHC on FFPE samples from 136 untreated metastatic melanoma pts, from 5 anatomical sites (liver, lung, brain, subcutaneous, and lymph node (LN)). Cell densities, subpopulations and the spatial distribution of cells were compared between sites. Results: CD3+ T cell infiltration was less dense in the liver (med = 154.3 cells/mm2) and brain mets (med = 180.7 cells/mm2) v's lung (med = 434.7 cells/mm2) and LN mets (med = 504.8 cells/mm2) (p<0.05), and T-cells were further away from melanoma cells in liver v's lung mets (med distance = 83µm v's 57µm respectively; P<0.05). The liver displayed a unique T-cell profile, with a significantly lower proportion of CD3+ T cells expressing PD-1 (med = 0.7%) compared to all other sites (P<0.05) while brain mets expressed the highest proportion of PD-1+ T cells (med = 8.9%). There were higher proportions of Tim3+ T cells in liver (10.7%) and lung mets (12.9%) v's brain, subcut and LN mets (P<0.05). Specifically, in liver mets CD3+ T cells within 20um of a melanoma cell had a significantly higher expression of Tim3 (med = 18.57%) v's PD-1 (med = 2%). Brain mets had the lowest density of CD68+ macrophages (med = 33 cells/mm2) v's lung (med = 372 cells/mm2), liver (med = 290 cells/mm2) and Subcut mets (med = 154 cells/mm2). Lung mets also had the highest proportion of PD-L1+ macrophages (med = 18.73%) compared to liver (med = 5.2%) and brain mets (med = 0.65%). While the most highly expressed T cell population varied between sites, CD16+ macrophages were consistently the highest expressed macrophage subpopulation regardless of metastatic site. Conclusion: These data suggest that liver mets are less immunogenic, with fewer T cells and greater distances between CD3+ T cells and melanoma cells, and may account for the poor prognosis of melanoma patients with liver metastases and their reduced response rate to immunotherapy compared to other mets. While liver mets have reduced PD-1 expression, higher Tim3 expression in the liver may provide a therapeutic opportunity to improve outcomes for pts with liver mets by using anti-TIM3 immunotherapy. Overall, these data provide novel insights into the site-specific biology of melanoma mets, heterogeneity in the tumor immune microenvironment, and the need for site specific biomarkers to be considered when selecting treatment targets. Citation Format: Jordan W. Conway, Robert V. Rawson, James S. Wilmott, Georgina V. Long, Richard A. Scolyer, Inês Pires Da Silva. Spatial distribution and immune cell infiltration at different sites of melanoma metastases (mets) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2762.

Abstract CT187: Overall survival (OS) by response during “induction” from the global, randomized Phase III IMvigor130 study of atezolizumab (atezo) + platinum/gemcitabine (plt/gem) vs placebo + plt/gem in patients (pts) with previously untreated metastatic urothelial carcinoma (mUC)

Abstract Background: IMvigor130 evaluated atezo + plt/gem (Arm A) vs placebo + plt/gem (Arm C) as 1L mUC treatment, allowing pts with at least SD to continue atezo or placebo “maintenance” after 4-6 cycles of plt/gem. The primary analysis showed statistically significant PFS benefit for Arm A vs C (Galsky Lancet 2020). The 1st interim OS data for Arm A vs C were encouraging but immature. This exploratory analysis used 2nd interim OS data (ITT median follow-up, 13.3 mo) to examine OS outcomes by response during atezo or placebo + chemo “induction” in Arm A vs C. Methods: Pts were randomized 1:1:1 to Arm A, B (atezo monotherapy) or C. In Arms A and C, chemo was gem + investigator's choice of cis or carbo. Co-primary EPs of PFS and OS in Arm A vs C (ITT) and OS in Arm B vs C (ITT and IC2/3) were tested hierarchically. This post hoc analysis evaluated post-induction (post-wk 18) OS in pts who completed 4-6 (but not >6) cycles of chemo without PD during induction (through wk 18), followed by ≥1 dose of atezo or placebo maintenance. Post-PD OS was evaluated in pts with PD during induction. HRs were adjusted to account for potential imbalances in known prognostic factors between arms. Results: Efficacy data are in the Table. Post-induction OS HR (95% CI) for pts with no PD was 0.86 (0.64, 1.16) (cis: 0.60 [0.35, 1.03], carbo: 0.97 [0.67, 1.41]). Post-progression OS HR for pts with PD was 0.74 (0.53, 1.03) (cis: 0.52 [0.28, 0.96], carbo: 0.78 [0.51, 1.18]). Conclusions: In this exploratory analysis from IMvigor130, OS benefit with atezo + plt/gem vs placebo + plt/gem in both pts with and without PD during induction was consistent with ITT results from the 1st interim analysis. Preliminary data suggest that cis-treated pts may derive greater OS benefit from adding atezo to chemo than carbo-treated pts, which warrants further investigation. OS follow-up is ongoing. IMvigor130 efficacy (second interim OS analysis)No PD during inductiona (post-induction OS)bPD during induction (post-progression OS)Arm A (n=166)Arm C (n=152)Arm A (n=91)Arm C (n=93)OS events, n (%)ITT97 (58.4)92 (60.5)82 (90.1)84 (90.3)Cisplatinc27/57 (47.4)35/59 (59.3)24/29 (82.8)30/33 (90.9)Carboplatinc70/109 (64.2)57/93 (61.3)58/62 (93.5)54/60 (90.0)Median OS (95% CI), moITT20.5 (17.6, 25.9)18.8 (14.4, 21.9)4.3 (3.5, 5.8)3.3 (2.5, 4.4)Cisplatin28.2 (19.8, NE)19.9 (11.0, 26.5)6.6 (4.8, 10.1)2.5 (1.6, 5.2)Carboplatin18.5 (12.9, 21.6)18.8 (12.9, 22.8)3.8 (3.2, 5.6)3.4 (2.6, 4.5)OS HR (95% CI)dITT0.86 (0.64, 1.16)0.74 (0.53, 1.03)Cisplatin0.60 (0.35, 1.03)0.52 (0.28, 0.96)Carboplatin0.97 (0.67, 1.41)0.78 (0.51, 1.18)Data cutoff: June 14, 2020. 1L, first-line; carbo, carboplatin; chemo, chemotherapy; cis, cisplatin; CR, complete response; EP, endpoint; HR; hazard ratio; ITT, intention to treat; mets, metastases; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease. a Pts who achieved at least SD (CR, PR, or SD without PD) during induction. b Post-week 18 OS. c Denominators refer to the number of pts in each chemotherapy subgroup/treatment arm. d Multivariable Cox proportional hazards model stratified by enrollment stage (1/2); adjusted for age, ECOG PS (0, 1, 2), cisplatin ineligibility (Y/N), liver mets (Y/N), lymph node mets only (Y/N), ≥3 metastatic sites (Y/N), renal impairment (Y/N), alkaline phosphatase ≥upper limit of normal (Y/N), glomerular filtration rate (<60 vs ≥60 mL/min), PD-L1 status (IC0/1, IC2/3), Bajorin risk score (0, 1, 2 and/or liver mets). For pts without PD, model was additionally adjusted for best response (CR, PR, SD) during induction. Citation Format: Enrique Grande, Aristotelis Bamias, Matthew D. Galsky, Eiji Kikuchi, Ian D. Davis, José Ángel Arranz, Arash Rezazadeh Kalebasty, Xavier Garcia del Muro, Se Hoon Park, Ugo De Giorgi, Boris Alekseev, Marina Mencinger, Kouji Izumi, Javier Puente, Jian-Ri Li, Xiaodong Shen, Beiying Ding, Qian Zhu, Jeremy Linsenmeier, Maria De Santis. Overall survival (OS) by response during “induction” from the global, randomized Phase III IMvigor130 study of atezolizumab (atezo) + platinum/gemcitabine (plt/gem) vs placebo + plt/gem in patients (pts) with previously untreated metastatic urothelial carcinoma (mUC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT187.

Association between sites of metastases (mets) and outcomes with immune checkpoint inhibitor (ICI) therapy for advanced urothelial carcinoma (aUC).

445 Background: Different metastatic sites have variable prognostic implications in aUC. However, details on response and outcomes with ICI for particular mets is still unknown. We hypothesized that bone and liver mets would have poor response and outcomes with ICIs. Methods: We performed a retrospective cohort study in patients (pts) with aUC who received ICI. We compared overall response rate (ORR) and overall survival (OS) between pts with different mets at ICI initiation. We developed 4 different models: 1) lymph node (LN) only vs other; 2) visceral mets (bone, lung, liver) vs other; 3) bone + liver mets vs bone without liver vs liver without bone vs neither and 4) 6 factor model: a. LN +/- soft tissue/locoregional recurrence b. lung +/- (a) c. bone +/- (b) d. liver +/- (c) e. central nervous system (CNS) +/- (d) and f. other. ORR and OS were compared among groups using multivariable (adjusting for ECOG PS and hemoglobin<10g/dl) logistic regression and cox regression, respectively. Results: We identified 984 pts (24 institutions); 703 and 696 were included in OS and ORR analyses, respectively. Median age at ICI start was 71 (range 32-93), 77% white race, 74% men, 67% ever smokers, 72% pure UC, 18% upper tract UC, 55% extirpative surgery. Prevalence of LN, lung, bone and liver mets at ICI start was 74%, 32%, 27% and 21%, respectively. LN-only mets had significantly higher ORR (44% vs 22%, OR 2.6, p<0.05) and longer mOS (22 vs 8 months, HR 0.5, p<0.05) vs other mets. Visceral mets had significantly lower ORR (21% vs 35%, OR 0.5, p<0.05) and shorter mOS (7 vs 17 months, HR 1.8, p<0.05) vs non-visceral mets. Pts with bone and liver mets had significantly lower ORR and shorter OS vs those with bone or liver mets, which both had significantly lower ORR and shorter OS vs those with neither and with LN +/- local recurrence (Table). Conclusions: In the context of ICI treatment, bone, liver, lung or CNS mets were associated with lower ORR and/or shorter OS, and bone and liver mets were particularly associated with low ORR and short OS. LN-only mets were associated with higher ORR and longer OS. Further work is needed to interrogate site-specific tumor-host immune interactions and identify biomarkers. Research Sponsor: None[Table: see text]

Staging laparoscopy for assessing inoperability in gastrointestinal malignancies: Is it useful?

Background: Despite the availability of modern cross-sectional diagnostic staging modalities, preoperative assessment of operability in intra-abdominal malignancy is often inadequate, especially in patients being considered for potential curative resection, resulting in many unnecessary laparotomies. Staging laparoscopy (SL) is usually undertaken in tertiary care centers, but the same has not been widely studied in India. The aim of the present study was to find out the possibility of diagnosing inoperability on SL and to study whether SL can prevent unnecessary laparotomy in cases of clinically diagnosed potentially resectable abdominal malignancies. Methods: This prospective diagnostics study was conducted in consecutive patients with gastrointestinal malignancies. All eligible patients were subjected to a thorough SL to look for inoperability before a therapeutic laparotomy. Statistical analysis of SL as a diagnostic modality was performed and the results were noted. Results: A total of 88 such patients were studied. The SL demonstrated inoperability in 24 out of the 88 (27.3%) patients. However, it failed to predict inoperability in 11 (12.5%) patients, yielding a sensitivity of 68.57% and specificity of 100%. The positive predictive value (PPV) of SL was 100%, whereas the negative predictive value (NPV) was 82.81% with efficacy of 87.5%. Conclusions: The specificity, PPV, NPV, and accuracy of SL to rule out inoperability in clinically diagnosed potentially resectable intra-abdominal gastrointestinal malignancies are noteworthy. The sensitivity of SL for the same purpose, though relatively low, may be augmented with practices such as liberal use of frozen section biopsy and intraoperative ultrasound. However, SL still fails to demonstrate unresectability due to locoregional advancement and aortocaval lymph node mets.

Veterans affairs (VA) prostate cancer treatment (Tx) sequencing (VAPCaTS): A real-world study.

54 Background: Limited real-world data are available on tx sequence for patients (pts) with metastatic hormone-sensitive PC (mHSPC) treated with androgen deprivation therapy (ADT) plus docetaxel (D) or abiraterone (A) who progress to metastatic castrate-resistant prostate cancer (mCRPC). Methods: VA electronic medical records were used to retrospectively analyze 240 men treated for mHSPC with ADT and D (n=208; selected to be overrepresented) from 07/2014-08/2018 or ADT and A (n=32) from 12/2016-09/2018 and receiving at least one tx after progressing to mCRPC. Results: For D and A cohorts respectively, median age at mHSPC diagnosis was 65.2 and 70.8 yrs; 62% and 77% were white; 98% and 100% had bone metastases (mets), 40% and 34% had lymph node mets, 21% and 16% had lung mets, and 20% and 6% had liver mets; median follow-up after ADT start was 2.2 and 1.4 yrs. Pts in D and A cohorts had 56% and 36% low, 33% and 45% intermediate, and 11% and 19% high Halabi risk scores at mCRPC, respectively. Among all pts, max mCRPC tx lines was 6; 106 (44%) had only one line, 71 (30%) had two lines, and 63 (26%) pts had ≥ three lines. Across all mCRPC tx lines, 71 (30%) received a taxane at some point (47 D, 40 cabazitaxel [C]). Txs for first and second line mCRPC are shown in the Table. For D pts who received androgen-receptor targeted agents (ARTA) as first mCRPC tx and received any second mCRPC tx, 70 (62%) were treated with back-to-back ARTA. For A pts, 25 (78%) received back-to-back ARTA as first mCRPC tx. Conclusions: Most pts received ARTA as first mCRPC tx, and a large proportion of pts were treated with back-to-back ARTA. Longer follow-up is needed to assess which sequences are associated with optimal outcomes.[Table: see text]

1979 GI Bleed Secondary to Gangliocytic Paraganglioma Treated With Radiation Monotherapy

INTRODUCTION: Gangliocytic Paraganglioma (GP) is a rare, usually benign tumor typically found in the 2nd part of the duodenum. The rarity of the tumor hasn’t allowed development of treatment guidelines. Mainstay of treatment involves endoscopic or surgical resection. Adjuvant chemotherapy or radiation has been utilized in a few cases. The case described is of a patient with GP presenting with hematochezia. The patient’s gastrointestinal (GI) bleed was treated with radiotherapy alone, which is the first case to our knowledge in the literature. CASE DESCRIPTION/METHODS: A 78 year old male with past medical history of multiple comorbid cardiovascular conditions and Multiple Myeloma presented with a six month history of hematochezia. Complete Blood Count showed a hemoglobin (hgb) of 8.6 g/dL with a baseline hgb of 11 g/dL four months prior. Esophagogastroduodenoscopy (EGD) showed a 3 cm ulcerated, friable periampullary mass. Biopsies demonstrated epithelioid, spindle and “large” cells associated with GP. Computed Tomography (CT) scan of the abdomen showed a 5.1 cm soft tissue density appearing to originate from the pancreatic head and abutting the duodenum with no regional lymphadenopathy or distant metastasis (mets). Due to the patient’s comorbidities and high perioperative mortality risk, radiation monotherapy was pursued for treatment. After fourteen radiotherapy sessions, the patient’s GI bleed resolved. Repeat EGD showed decreased vascular markings in the duodenal mass. DISCUSSION: GP is a rare tumor composed of epithelioid, spindle and ganglion cells. Tumor behavior is usually benign with rare invasion of nearby structures and lymph node mets. CT scan and endoscopic ultrasound (EUS) are generally recommended for staging. Our patient underwent CT Scan, but EUS was deferred due to little utility with an increased perioperative mortality. Local surgical resection is the most common treatment, but endoscopic resection has shown lower morbidity and mortality in selected cases. The size of the tumor and invasion depth dictates treatment modality. Our patient’s tumor size (>5 cm) and pancreatic head origin would have necessitated pancreaticoduodenectomy in a healthy patient. Due to his comorbid conditions and positive literature data on adjuvant radiotherapy for benign paragangliomas of the pancreatic head and neck, our patient underwent successful monotherapy with radiation for control of bleeding. This case shows benefit of radiotherapy alone for control of bleeding due to GP in high risk surgical patients.

Clinical prognostic score of BRAF V600E mutated (BM) metastatic colorectal cancer (mCRC): Results from the “BRAF, BeCool” platform.

639 Background: BM mCRCs account around 10% of mCRCs, with a dismal prognosis. Intra-group heterogeneity has been recently studied, however, an extensive prognostic clinical analysis has not been provided yet. Methods: BM mCRCs tested on primary tumor (T) or on metastases (mets) were collected from 13 Italian Oncology Units. A prognostic score was derived by an internal cross-validation procedure: the whole population was splitted in a training (67%) and in a testing (33%) sample; this process was repeated 10 times. Primary endpoint was OS. Multivariate analysis (MA) was performed on each training sample, and covariates with independent prognostic value were included in the scoring system, assigning rounded scores to the covariates. Results: A total of 395 BM mCRC patients were included. At MA, independent prognosticators for OS were ECOG PS (1 vs 0; 2-3 vs 0), Ca19.9 (high vs normal); LDH (≥300 vs low); neutrophil/lymphocyte ratio ( > 3 vs low); T grading (3-4 vs 1-2); liver mets (yes vs no); lung mets (yes vs no); lymphnode mets (yes vs no). Two different scoring systems were built: a «complete» score (0-18) with all significant covariates; a «simplified» score (0-11), selecting only significant clinico-pathological covariates, excluding laboratory values. With «complete» score, proportion of patients with low (0-4), intermediate (5-8) and high (9-18) score was 39%, 46% and 15%, respectively. Median OS was 27.6, 18.7 (HR interm. vs low 1.89, 95%CI 1.25 – 2.86, p = 0.003) and 6.6 months (HR high vs low 4.95, 95%CI 2.89 – 8.47, p < 0.0001), respectively. Similar results were observed adjusting for type of first-line treatment. Median PFS was 11.1, 8.6 (HR interm. vs low 1.36, 95%CI 0.94 – 1.97, p = 0.11) and 4.1 months (HR high vs low 3.50, 95%CI 1.98 – 6.20, p < 0.0001). Similar results were obtained with the «simplified» score. Conclusions: A simple and ready-to-use prognostic score for BM mCRC was developed. The robustness of the internal cross-validation justifies the effort of a validation study. Identification of specific prognostic factors in distinct molecular subgroups is crucial for adjusting exploratory translational analyses and future clinical trial design.

Phosphoproteomic analysis of matched primary breast cancer (BC) and lymph node (LN) metastases.

11620 Background: Therapeutic recommendations are often based on molecular markers expressed in primary BCs. However, LN metastases (mets) may more accurately reflect the lethal potential of the disease (Ries 2007). Whether activated oncogenic pathways in axillary LN mets can be reliably identified in the associated primary BCs is unknown. We evaluated the activation of key signaling pathways in pts’ matched primary BC and axillary LN mets using reverse phase protein array (RPPA). Methods: 60 pts’ matched FFPE primary BC and axillary LN mets (20 TN, 20 ER+/HER2-, 20 HER2+) are to be evaluated by RPPA at a CLIA-certified laboratory. The first 20 matched BC/LN (3 TN, 14 ER+/HER2-, 3 HER2+) and 7 unmatched (1 TN LN, 1 ER+/HER2- BC, 5 ER+/HER2- LN) results are reported here. Immunostaining of 14 HER1/2/3 and downstream pathway proteins was performed. Mann-Whitney U tests (p value) were utilized to compare BC vs LN mets protein level. Results: Increased expression of HER1 (6-fold) and p-Akt (2-fold) was observed in TN compared to Luminal (Lum) and HER2+ primary BCs. AR expression was upregulated in TN and HER2+ (2-fold) compared to Lum primary BCs. The LN mets showed higher expression of HER1 (p = 0.004), p-HER3 (p = 0.040), p-IGFR (p = 0.009), p-S6 (p = 0.033), p-4EBP1 (p = 0.027) and p-MEK1/2 (p = 0.023) compared to primary BCs. TN had higher level of p-Akt T308 (p = 0.077) in the LN mets compared to the primary BCs while HER2+ showed a downregulation of p-Akt T308 (p = 0.049) in the LN mets. HER2+ also had higher level of HER1 (p = 0.049), p-HER3 (p = 0.049), p-FGFR (p = 0.083), and p-4EBP1 (p = 0.049) in the LN mets compared to primary BCs. Higher levels of HER1 (p = 0.043) and p-MEK1/2 (p = 0.027) were observed in Lum B LN mets compared to p-IGFR (p = 0.041), p-Akt S473 (p = 0.088), p-S6 (p = 0.063) and p-4EBP1 (p = 0.097) in Lum A LN mets. Conclusions: In TNBC, preliminary results show that p-Akt is differentially upregulated in LN mets while HER1, p-HER3 and p-4EBP1 are overexpressed in HER2+ LN mets. Lum A LN mets showed higher levels of p-IGFR, p-Akt, p-S6 and p-4EBP1 vs Lum B LN mets which had higher levels of HER1 and p-MEK1/2. These data suggest different signaling pathways in BC LN mets compared to primary BCs. Analyses of 60 pts’ matched primary BC/LN samples will be presented.

Abstract CT140: Pilot study of “hyperfractionated” anti-prostate specific membrane antigen (PSMA) radioimmunotherapy (177Lu-J591) for progressive metastatic castration-resistant prostate cancer (mCRPC)

Abstract Background: Phase I and II single dose 177Lu?J591 studies have been published demonstrating safety and efficacy in mCRPC. We reported a study of fractionated-double dose 177Lu?J591 (2 doses given 2 weeks apart), demonstrating the ability to administer higher cumulative doses with a dose-response and also equal or less toxicity. As a single-dose, 70 mCi/m2 results in at least 30% declines in 47% with 41% receiving a platelet transfusion. When administered in 2 divided doses, 80 mCi/m2 results in 25% PSA response with 25% transfusion; 90 mCi/m2 results in 59% response with 65% getting transfused. We hypothesize that additional dose-fractionation will allow a higher cumulative dose with less toxicity. Methods: Patients with progressive mCRPC with normal neutrophil and platelet counts were enrolled in a planned 6-patient pilot study. No selection for PSMA expression was performed. 177Lu-J591 was administered at 25 mCi/m2 every 2 weeks until the emergence of grade 2 myelosuppression. Planar imaging of 177Lu?J591 at 6?8 days following the 1st and 4th doses was performed. Pre- and post-treatment PSA and CTC counts (CellSearch) were measured. Results: 6 men median age 68.5 (range 50-79), PSA 84.8 (14.7-2265), 67% elevated LDH, 83% unfavorable CTC count, 67% prior chemo, all prior exposure to abi/enza. Five (83%) with bone mets, 5 (83%) with lymph node mets, and 2 (33%) with visceral mets. Pts received a range of 3-6 doses (cumulative 75-150 mCi/m2 of 177Lu-J591). Two (33%) had >30% PSA decline and 3 (50%) had CTC count decline. Two (33%) experienced Gr 4 neutropenia (without fever), 3 (50%) had Gr 4 thrombocytopenia, and 2 (33%) had platelet transfusion. Two had worsening cytopenia following partial count recovery during periods of cancer progression, with bone marrow biopsies in both revealing infiltrative tumor without dysplasia. Targeting of 177Lu?J591 at known sites of disease was seen in all (100%) pts. Conclusions: “Hyperfractionation” of radioimmunotherapy with 177Lu?J591 is possible in a heavily pre-treated population with poor prognostic features. Targeted delivery of 177Lu occurs to known sites of disease in an unselected patient population. Study is ongoing to determine the optimal target population and dosing regimen for phase 2 study. Citation Format: Ana M. Molina, Jaspreet S. Batra, Beerinder S. Karir, Yuliya Jhanwar, Shankar Vallabhajosula, Paul J. Christos, Linda Lam, Jennifer Epstein, Irene Karpenko, Himisha Beltran, David M. Nanus, Stanley J. Goldsmith, Neil H. Bander, Scott T. Tagawa. Pilot study of “hyperfractionated” anti-prostate specific membrane antigen (PSMA) radioimmunotherapy (177Lu-J591) for progressive metastatic castration-resistant prostate cancer (mCRPC). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT140.

Abstract P3-07-38: Increment of neutrophil/lymphocyte ratio (NLR) can be one of the useful predictive markers for the metastatic breast cancer (MBC) with first line hormonal therapy (HT)

Abstract [Introduction] Cancer microenvironment formed by the immune and inflammatory cells is noticed to be one of the factors for tumor growth, invasion or metastasis. To figure out the systemic inflammatory environment, the neutrophil / lymphocyte ratio (NLR) is a useful method and a simple indicator. We have some reports that NLR can predict the prognosis in many malignancies, including breast cancer, as I reported in SABCS 2014, however, NLR cannot be a predictive marker in major cancers, because the usage with anti-cancer agents will make NLR status out of order. In hormonal receptor positive metastatic breast cancer (HR+ve MBC), we choice hormonal therapy (HT) for the first line, mainly. HTs have little influence for NLR, therefore, the change of NLR, increment or decrement, can reflect the systemic inflammatory status and be a useful predictive marker for the HR+ve MBC with HTs. [Purpose] I define dNLR as the difference between NLR at the 2-3 months after HT and before HT. To evaluate the dNLR affects the Overall Survival (OS) and Progression Free Survival (PFS) of the patients of MBC or not. [Patients] From 2003 to 2013, we have 299 MBC patients in our hospital. Out of them, 134 patients had HTs as first line, included 18 Stage4 patients at the first visit. Median Disease free survival (DFS) is 1497-day, the median OS after the recurrence is 1472-day. Average value of the NLR before HT is 2.62. The reasons of MBC are bone metastases (mets), pleural and pulmonary mets, liver mets, lymph node mets, central nervous system (CNS) mets, unresectable metastatic chest wall recurrence, or other. [Results] By univariate analysis, DFS < 1000 (p<0.01) and liver mets (p<0.05) made a contribution to poor OS. dNLR>=0.5 (p<0.05), liver mets (p<0.05) and 2 or more organs involvements (p < 0.05) made a contribution to poor PFS. With multivariate analysis, for OS, only DFS < 1000 was an independent prognostic factor. And for PFS, only dNLR>=0.5 was an independent predictive factor. Poor OS factors by univariate analysis had no influence for PFS as well as poor PFS factors did not reflect the OS. [Discussion] The dNLR was a predictive marker for HR+ve MBC which we can easily and simply examine by blood sample. Now we cannot reveal the relationship with dNLR and OS, however, this fact suggests that we can decide to stop the first line HT and select the second line therapy using with not only images or tumor makers but also dNLR. This can certainly contribute for good OS. It remains some questions between dNLR and other examinations, for example, which can detect the patient status earlier and more accurate? First, we need to accumulate further retrospective cases and plan the prospective study to make sure of the adequate treatment divided by dNLR. [Conclusion] The dNLR>=0.5 is one of the independent predictive markers for HR+ve MBC with first line HT. Citation Format: Miyamoto T, Fujisawa T, Morishita A, Yanagita Y, Kuwano H. Increment of neutrophil/lymphocyte ratio (NLR) can be one of the useful predictive markers for the metastatic breast cancer (MBC) with first line hormonal therapy (HT). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-38.

Programmed death-ligand 1 (PD-L1) expression in cured and not cured testicular and other germ cell tumors (GCT).

485 Background: PD-L1 is involved in immune regulation and is prognostic in many tumor types. The aim of this study was to assess PD-L1 expression in orchiectomy and metastases (mets) from GCT and to assess for an association with outcome. Methods: Immunohistochemistry (IHC) on whole sections from archival formalin-fixed paraffin-embedded tissue from Dana-Farber Cancer Institute (DFCI) and Gustave Roussy (IGR) was performed using anti-PD-L1 antibody E1L3N. Stained slides were scored semi-quantitatively and assessed independently. At DFCI, PD-L1 was scored as percent of positive tumor cells (TC) and extent of positive immune cell (IC) infiltrate; at IGR, a cut-off of 5% defined positive TC and IC. PD-L1 status was assessed by site, histology and chemotherapy (CT) status. PD-L1 status was correlated with clinical outcome. Most samples at DFCI were pre-CT (74.2%) whereas most at IGR were post-CT (85.4%). Results: IHC from 171 patients with GCT (89 DFCI, 82 IGR) from 1987-2014 was reviewed. The DFCI cohort included 69 orchiectomy, 15 mets and 5 unknown origin with 28 total deaths; the IGR cohort included 26 lung mets, 36 mediastinal or retroperitoneal lymph node mets and 20 primary mediastinal tumors. DFCI had 38 seminoma (S), 50 nonseminoma (NS) and 1 unknown; at IGR, 13 S and 69 NS. In both cohorts, PD-L1 staining in IC was higher in S (DFCI 33/38 moderate (mod)-high (86.8%); IGR 12/13 positive (92.3%)) vs. NS (DFCI 26/50 mod-high (52.0%); IGR 35/68 positive (51.5%)) (DFCI p = 0.003; IGR p = 0.006). At DFCI, 5 samples had PD-L1 positive TC (2 mixed GCT, 2 pure choriocarcinomas (CC) and 1 S); at IGR, 14 had positive TC (all NS, including 11 pure CC). More PD-L1 positive TC were CC than other GCT types (DFCI p = 0.003; IGR p < 0.001). In 36 S orchiectomy samples at DFCI, 0/4 that scored none-mild died and 2/31 (6.5%) that scored mod-high died (p = 1.00); in 30 NS orchiectomy samples, 4/9 (44.4%) that scored none-mild died and 2/16 (12.5%) that scored mod-high died (p = 0.14). Conclusions: Higher PD-L1 status in orchiectomy is not associated with GCT survival. PD-L1 positive TC may serve as a histological marker for CC among NS. Higher PD-L1 expression on IC in S and on TC in CC may point to immunotherapy as a therapeutic option in these tumors.

3-year safety follow-up of radium-223 dichloride (Ra-223) in patients (Pts) with castration-resistant prostate cancer (CRPC) and symptomatic bone metastases (Mets) from ALSYMPCA.

195 Background: In ALSYMPCA, the first-in-class α-emitter Ra-223 had a highly favorable safety profile and was well tolerated. Safety monitoring of Ra-223 is essential for a complete safety profile. Here are final safety data including long-term follow-up safety 3 years after last pt’s first injection (inj). Methods: Pts received 6 inj and entered designated follow-up from 4 wks after their last inj to 3 years after first inj. Pts were to be evaluated during tx period and 9 follow-up visits. All adverse events (AEs) were collected until 12 wks after last inj; thereafter, only AEs deemed tx-related were collected. Additional long-term safety data were assessed by specific diseases including acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), aplastic anemia, and new primary cancer in bone or other organs. Results: Safety population (pts receiving ≥ 1 inj) included 901 pts (Ra-223, n = 600; placebo [pbo], n = 301); 572 pts (Ra-223, n = 405; pbo, n = 167) entered follow-up. 60 pts (Ra-223, n = 49; pbo, n = 11) completed all follow-up visits. Overall, 564 (94%) Ra-223 and 292 (97%) pbo pts had ≥ 1 tx-emergent AE (Table). During long-term follow-up, there were no reports of AML, MDS, or new primary bone cancer. New primary cancers in other organs were reported: 2 Ra-223 (1 bladder, 1 lymph node mets), 3 pbo (2 skin, 1 adenocarcinoma rectum and sigmoideum), and 2 pbo cross-over pts (1 skin, 1 meningioma). Aplastic anemia was reported in 1 Ra-223 pt. Conclusions: Ra-223 remained safe and well tolerated 3 years after the last pt’s first inj. No major safety issues were identified during the ALSYMPCA 3-year long-term follow-up. Clinical trial information: NCT00699751. [Table: see text]

Abstract 4177: Identification of pathways relevant for metastatic site prediction in prostate cancer

Abstract Background and Significance: We address the problem of metastatic site prediction in prostate adenocarcinoma (PRAD), with a specific focus on identifying molecular pathways that are activated in association with the homing to a particular metastatic site. The approach can reveal the molecular mechanisms in metastatic cancer while also providing clues about potential drug targets. Further experimental validation of our findings may lead to the discovery of novel therapies for patients who are in the advanced stages of disease. Methods: We downloaded four PRAD datasets that contained met-site information from the Gene Expression Omnibus (GEO) and trained multi-class predictors on this set. The predictors were then evaluated on patient samples collected as part of the Stand Up To Cancer (SU2C) initiative. Standard normalization techniques were used to remove batch effects associated with non-biological factors such as the institution from which the materials were collected and/or assays conducted. We focused our attention on linear models due to their straightforward interpretation: higher weights indicate stronger association of the corresponding genomic features with a particular metastatic site. To identify pathways implicated by the relevant genomic features, we employed model regularization via group LASSO. This technique groups genes according to their pathway membership using the PathwayCommons database. The regularizer (penalty trading accurate classification with model complexity) sets the weights of an entire group to zero if those groups were uninformative for met-site prediction and non-zero otherwise. Results: We trained a multi-class linear predictor to recognize lymphatic node, liver and bone metastatic sites from gene expression data. The resulting model gave rise to two linear signatures: one that distinguished liver mets from the rest, and another that distinguished lymph node mets from the rest. The signatures were enriched for pathways commonly associated with liver development and liver progenitor cells, as well as pathways involved in integrin interactions on the cell surface. Based on the latter, we hypothesize that the up-regulation of particular integrin-signaling pathways may be responsible for driving the tendency of metastatic PRAD cells to prefer one site over another. We are currently in the process of investigating whether there is further evidence of this hypothesis in the SU2C data, as well as comparing group LASSO to other regularization techniques that also incorporate prior pathway information. Conclusion: We used linear methods to identify several pathways that may be responsible for localization of metastatic prostate adenocarcinoma cells to specific tissues. Our empirical results provide evidence that integrin-signaling may play a key role in this process. We are working on robustness evaluation of these findings, as well as experimental validation with our SU2C collaborators. Citation Format: Adrian Bivol, Kiley Graim, Evan Paull, Dan Carlin, Robert Baertsch, Artem Sokolov, Josh Stuart. Identification of pathways relevant for metastatic site prediction in prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4177. doi:10.1158/1538-7445.AM2014-4177

Trastuzumab (TRA) in combination with different first-line chemotherapies for treatment of HER2-positive metastatic gastric or gastroesophageal junction cancer (MGC): Findings from the German noninterventional observational study HerMES.

4065 Background: The international phase III study ToGA has recently shown that TRA is effective in prolonging survival in HER2-positive MGC. However, few data are available for TRA as part of routine clinical practice. Methods: This non-interventional observational study was conducted to evaluate the efficacy, safety and feasibility of TRA in previously untreated pts with HER2-positive MGC. Results: Between Apr 2010 and Jan 2012, data from 110 pts were collected. All pts were evaluable for safety. Baseline pt characteristics were as follows: median age 63 yrs (range 29–88); gender (male 70%; female 29%); ECOG PS (0: 25%; 1: 50%; 2: 15%; 3: 5%); distant mets (91%); liver mets (54%), lymph node mets (35%); peritoneal carcinomatosis (23%). The median duration of TRA treatment was 4.4 months (0–17.1). According to the schedule of chemotherapy TRA was administered every 2–3 wks in a median dose of 4–6 mg/kg BW. Only 28% of pts received TRA according to the label in combination with cisplatin and 5-FU or capecitabine. The remainder received: cisplatin, 5-FU and leucovorin (17%); 5-FU, leucovorin, oxaliplatin and docetaxel (8%); 5-FU, leucovorin and oxaliplatin (7%); capecitabine (6%); other combinations (25%); TRA monotherapy (7%). Although most pts didn’t receive cisplatin-based therapy, preliminary median progression-free survival was 6.8 months, thus comparable to the ToGA data. Most common adverse events (AEs, all grades) were diarrhoea (7%), vomiting (5%) and nausea (5%). Most common grade 3/4 AEs were vomiting (3%), nausea (2%) and fatigue (2%). Health-related quality of life as assessed by EORTC QLQ-C30 and QLQ-STO22 remained stable during observation time. An updated analysis of approx. 200 pts will be presented at the meeting. Conclusions: TRA combined with diverse chemotherapies is safe and effective in the routine treatment of MGC. Cisplatin-free less toxic regimens are feasible and equally effective. The results are in line with those from the ToGA trial and suggest that treatment with TRA should be regarded as standard of care for pts with HER2-positive MGC.

Radiation Therapy Oncology Group (RTOG) 9413: Randomized trial comparing whole pelvic radiotherapy (WPRT) to prostate only (PORT) and neoadjuvant hormone therapy (NHT) to adjuvant hormone therapy (AHT).

96 Background: RTOG 9413 demonstrated that NHT+WPRT improved progression-free survival (PFS) compared to NHT+PORT, WPRT+AHT and PORT+AHT. We update primary and secondary endpoints (SE): biochemical failure (BF), time to metastasis (Mets), prostate specific survival (PSS) and overall survival (OS). Methods: RTOG 9413 opened on April 1, 1995, and closed on June 1, 1999, with 1275 eligible pts who were required to have a risk of lymph node (LN) involvement >15% but LN-positive pts were ineligible. They were stratified by T Stage, GS (<7 vs 7-10) and PSA (>30 vs < 30ng/ml) and randomized to PORT +/- WPRT to 70 Gy and NHT or AHT. Hormonal therapy (HT) consisted of flutamide, and leuprolide or goserelin, monthly x 4 mos, beginning 2 mos before RT and continued until RT is completed (NHT) or beginning at the completion of RT (AHT). For this analysis PFS was defined as the first occurrence of local/regional or LN progression, Mets, BF (PSA nadir+2ng/mL), or death from any cause. PSS is defined as a death due to prostate cancer, treatment toxicity or unknown causes with local progression, Mets or BF. Results: For the entire cohort WPRT or NHT did not appear to improve any endpoint compared with PORT or AHT, (although there was a trend for improvement in regional failure for WPRT vs PORT, (p=0.07)). However, there were complex sequence/volume dependent interactions between HT and RT and statistically significant differences between the 4 arms in PFS (p=0.03). There was a trend for NHT+WPRT to improved PFS compared to NHT+PO (p=0.07) and WPRT+AHT (p=0.04). NHT+WPRT was associated with an increased risk of late GI toxicity, 5% compared to 0.6%, 2% and 2% for NHT+PORT, WPRT+AHT and PORT+AHT (p<0.001) but not in GU late toxicity. Conclusions: The failure to improve SE or definitively impact PFS may reflect sample size, pt selection, and inadequate RT doses. RTOG 0924 will test the hypotheses that modern techniques and doses will improve OS without increasing late toxicity.

Value of quantitative DNA fingerprinting in classification of second breast tumors and association with outcome.

10552 Background: Management of second breast tumors is challenging. Recent data suggest that second breast tumors may be associated with worse outcomes compared to initial tumors, implying that some second tumors may be recurrences or metastases (mets). We hypothesize that quantitative DNA fingerprinting may improve classification of second breast tumors as independent primaries vs mets, affecting prognosis and treatment. Methods: We modified our published DNA fingerprinting assay into a high throughput platform to generate scores quantifying genetic differences between breast tumors. Higher scores reflect difference. With IRB approval, we collected samples and data from 34 patients (pts): 20 had ipsilateral lymph node (LN) mets and 19 had > 1 breast tumor. We modeled independent primaries using pairs of tumors from different pts. We modeled mets using pairs of tumors and LN mets from the same pt. We generated a receiver operator curve (ROC) of the scores to classify any tumor pair as independent primaries, mets, or indeterminate. We then classified tumor pairs from pts with > 1 breast tumor and followed them until disease progression. Results: We performed quantitative DNA fingerprinting on 181 tumor and LN mets samples. Scores of pairs of tumors from different pts (n = 420) averaged 0.606. Scores of pairs of tumors and their LN mets (n = 20) averaged -0.091. These scores differed (p < 10-25, student's T-test). Based on the ROC (area under the curve 0.975), scores > 0.227 were independent primaries and scores < 0.187 were mets with 95% sensitivity. For pts with > 1 breast tumor, clinical diagnosis of the second tumor (as independent primary or met) was often indeterminate (11/19 cases, 58%) and did not predict outcome. Genetic scoring decreased indeterminate cases (2/19 cases, 11%). Kaplan Meier analysis at 60 months suggested that pts with second tumors genetically classified as an independent primaries progressed later (47 vs 25 months), although this did not reach significance (p = 0.21, log rank test). Conclusions: Quantitative DNA fingerprinting improves classification of second breast tumors into independent primaries vs mets. With further refinement, this classification may also predict progression. No significant financial relationships to disclose.

Abstract 2329: Alterations in laminin expression modulate prostate cancer cell behavior through changes in integrin and insulin-like growth factor receptor actions

Abstract Introduction: During development of primary prostate carcinomas alterations to the extracellular matrix occur, including a loss of laminin 332 (LM332) and one of its cell surface receptors, β4 integrin. There are few published studies on what the laminin composition of metastases may be or how alterations in laminin expression affect prostate cancer cell behavior. Expression of the insulin-like growth factor receptor (IGF-IR) also is altered in prostate cancer progression and some studies suggest cross-talk between integrins and IGF-IR. Purpose: To determine if laminin and integrin expression is altered in prostate cancer metastases and how these alterations affect prostate cancer cell behavior in light of the interactions between integrins and IGF-IR. Methods: We performed immunofluorescent (IF) staining on tissue samples of primary PCa and metastases. We also used various prostate cancer cell lines, including M12 cells transfected with the LMα4, β2, or α4β2 chains, to perform adhesion, migration, and proliferation assays in the presence of inhibitory integrin and IGF-IR antibodies. Results: Our IF staining demonstrated that in addition to a loss in LM332 expression, the LMα4 and β2 chains were absent from the prostate basal membrane in primary prostate tumors. Expression of the LMα5 and β1γ1 chains was retained in primary tumors as well as in lymph node metastases. We saw a loss of β4 integrin in primary tumors as well as in metastatic cancer, but α6 and β1 integrins were retained; in lymph node mets, α2 and α3 integrins also were expressed. For M12 laminin cells, enhanced adhesion to both collagen and fibronectin was further increased by treatment with the inhibitory IGF-IR antibody A12. An inhibitory β1 integrin antibody, but not individual alpha integrin antibodies, blocked this enhancement. Inhibitory β1 as well as alpha integrin antibodies blocked adhesion of the empty-vector control cells. Similar results were obtained for cell migration studies using a scratch-assay. Staining of cells following exposure to A12 showed there was an increase in LM332 and LMβ1γ1 expression compared to untreated cells, which may account for the increased adhesion and migration following A12 treatment. We then examined laminin expression of various prostate cancer cell lines: LNCaP, LNCaP C4-2, PC3, and DU145. We found no expression of LM332 in any of these lines. Cytoplasmic expression of the LMβ1γ1 and LMβ2 (LNCaP lines) chains was detected, but deposition of these laminins was not present. These lines demonstrated increased adhesion to laminin-rich ECM compared with adhesion to fibronectin or collagen. And these lines showed enhanced proliferation when grown on laminin-rich ECM from the M12 laminin cells. Summary: Alterations in laminins affect the adhesion, migration, and proliferation of prostate cancer cells, in part, through integrin and IGF-IR actions. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2329.

Evaluation of radiologic diagnosis in peripheral clinical IA lung cancers—A prospective study for radiological diagnosis of peripheral early lung cancer (JCOG 0201)

7220 Background: The spread of computed tomography (CT) screening for lung cancer (LC) leads to the increased detection of small sized LC. Performance and accuracy of radiological diagnosis had not been evaluated and indication of limited surgery for CT detected LC remains unknown. Methods: Between Dec/2002 and May/2004, a prospective study was performed. Patients (pts) having peripheral lung adenocarcinoma (AD) of T1N0M0 were eligible. Radiologic findings of LC were evaluated as to ground-glass opacity (GGO) with thin-section CT (TSCT). A radiological non-invasive cancer (NIC) was defined as a tumor having consolidation less than half of the maximum tumor dimension. A pathological NIC, which is future candidate for limited surgery, was defined as a tumor with no lymph node mets, lymphatic, nor vascular invasion. A validity of radiological diagnosis by above criteria was investigated. Primary endpoint is specificity as the proportion of pts with radiologically diagnosed invasive LC in pts with pathologically diagnosed invasive LC. Planned sample size was 450 with precision-base. We expected that lower limit of 95% CI of specificity is over 97%. Results: Totally 811 pts were enrolled onto the study at 31 institutions, including 357 men. Age ranged 27 to 75 (median 61). Primary endpoint was evaluated on central-reviewed 545 AD resected by lobectomy. Specificity and sensitivity for the diagnosis of pathological NIC were 96.4% (161/167 95% CI 92.3% to 98.7%) and 30.4% (115/378 95% CI 25.8% to 35.3%), respectively. As to relationship between radiologic NIC and pathological nodal involvement, specificity and sensitivity for the diagnosis were 98.3% (59/60 95% CI 91.1% to 100%) and 24.7% (120/485 95% CI 21.0% to 28.8%), respectively. Conclusions: Our pre-determined criterion for the specificity was not confirmed, and candidates for limited surgical resection can not be selected based on our criteria. However, radiological diagnosis of node-negative LC with TSCT was well coincide, and the criterion might be used for selecting node negative peripheral LC. A phase II study of limited surgical resection for peripheral LC 2.0 cm or less in size is now planned based on the results of exploratory analysis of this study. No significant financial relationships to disclose.