tbuckley/cabot-search huggingface dataset:
Clinical significance of FDG-PET/CT in assessment of recurrence in breast cancer patients before surgery.
Authors: Ayuha Yoshizawa, Kazushige Futsuhara, Koichi Suzuki, Tomohisa Okochi, Toshiki Rikiyama, Nao Kakizawa
Journal: Journal of Clinical Oncology (2017)

e23215 Background: FDG-PET/CT is widely used for the detection of primary breast cancer and metastasis, although its clinical significance is somewhat restricted to appropriate higher-risk populations. We attempted to apply maximum uptake values (SUV max ) of FDG-PET/CT to assess the malignant potential of breast cancer before surgery. Methods: We retrospectively reviewed 187 consecutive patients with invasive breast cancer and no distant metastasis recruited from 2009 to 2011 in our hospital who underwent PET/CT before surgery, and determined the representative PET imaging features by SUV max . Correlation of SUV max with several clinicopathological factors was evaluated by regression analysis. Relapse-free survival (RFS) and overall survival (OS) were compared among these factors and SUV max using univariate and multivariate Cox analysis, Kaplan-Meier curves, and log-rank tests. Results: All patients were women of median age 60 years. The median follow-up period was 72 months. A logarithmic transformation was applied to SUV max , which resulted in exclusion of 32 patients with no FDG uptake on PET/CT. Regression analysis revealed that SUV max significantly correlated with ER (P = 0.0138), HER2 (P = 0.0153), lymph node metastasis (P &lt; 0.0001), and tumor size (P &lt; 0.0001). Multivariate analysis showed that tumor size was a significant independent factor. As regression analysis showed a strong correlation between SUV max and tumor size &lt; 5 cm (P &lt; 0.0001), the 11 patients with tumor &gt; 5 cm were excluded. Concerning the malignant potential of tumors, RFS was evaluated by univariate analysis whereby the median log SUV max (0.6) was the only significantly independent factor to predict recurrence (P = 0.045). Patients with log SUV max &gt; 0.6 showed poor RFS (11 patients with recurrence) compared with log SUV max &lt; 0.6 (2 patients with recurrence) (P = 0.0064). OS showed no significant correlation. Conclusions: PET/CT is potentially a valuable modality to predict tumor recurrence in patients with breast cancer whose tumor size is &lt; 5 cm and demonstrates uptake before surgery.
Automated bone scan index as an imaging biomarker in metastatic castration resistant prostate cancer (mCRPC) patients treated with radium-223.
Authors: Aseem Anand, Stephanie Daignault, Luke T. Nordquist, Jorge Ramos, Rohit K. Jain, Matthew McDonald, Gregory Campbell, Saby George, Costantine Albany, Evan Y. Yu, Anders Bjartell, Ajjai Shivaram Alva
Journal: Journal of Clinical Oncology (2016)

e16600 Background: There are no validated imaging tools to assess response to the Radium-223 (Ra 223). In this study, we explored the analytically validated automated bone scan index (auto-BSI) as an imaging biomarker in mCRPC Patients (Pts) treated with Ra-223. Methods: In a multi-center retrospective study, available bone scans of mCRPC Pts treated with Ra 223, were collected at baseline (BL) and at treatment follow-up (Tx-FU). The auto-BSI was analyzed using the EXINIboneBSI version 2. Logistic regression, cox regression and Kaplan Meier analyses evaluated the auto-BSI associations with PSA response, defined as 50% decline from BL; pain response, defined as decrease in the VAS score from BL; Alkaline phosphatase (ALP) response, defined as 30% decline from BL; and with overall survival (OS). Results: Of144 Pts treated with Ra223, 66 (46%) had a BL bone scan and 25 of them also had a Tx-FU bone scan taken 18 to 30 weeks after the first treatment. No significant differences were observed in BL characteristics of Pts with bone scans versus without. The median number of ra223 doses were 6 (1-6). Median BL auto-BSI was 2.4 (range:0.01–33.2) and median Tx-FU auto-BSI was 0.5 (range:0-20.1). The BL auto-BSI was associated with OS (HR = 1.4; 95%CI = 1.1-2.0) and with ALP response (HR = 1.6; 95%CI = 1.04-2.4), p = 0.02. BL auto-BSI was not associated with pain, p = 0.48, or with PSA response, p = 0.76. OS at 9 months with BL auto-BSI < 5 was 76% vs. 40% in Pts with BSI > 5. In Tx-FU analysis, 17 (68%) of the 25 Pts had ≥ 30% decrease in auto-BSI from BL; Only 5 (20%) Pts were PSA responders, and all 5 Pts had ≥ 30% decrease in auto-BSI. Conclusions: Baseline auto-BSI was associated with OS and with ALP response. The findings encourage prospective investigations to validate the role of BSI as an imaging biomarker in mCRPC Pts being treated with Ra-223.
Germline BRCA mutations (gBRCAmut) on breast cancer (BC) outcomes: A large meta-analysis.
Authors: Ruben Quek, Jack Mardekian, Caroline Burk
Journal: Journal of Clinical Oncology (2018)

e12575 Background: Past studies evaluating prognosis of gBRCAmut status in BC patients have had inconsistent results. We summarized existing systematic literature reviews and performed a meta-analysis of available evidence of the effect of gBRCAmut on multiple survival outcomes of BC pts as a whole and in specific subgroups of interest, including disease stages and HR+/HER2- status. Methods: Seven systematic literature reviews identified 35 unique studies that met all inclusion criteria and were considered for this meta-analysis. These studies involved 19,860 BC pts; 1998 (10.1%) were gBRCAmut carriers. Each study’s log hazard ratio (HR) and log standard error served as inputs in the meta-analysis. The associations between gBRCAmut status and overall survival (OS), recurrence-free survival (RFS), and distant metastasis-free survival (DMFS) were evaluated separately in 17 studies in stage I–III pts for each outcome using fixed-effect models. The association between gBRCAmut status and OS was evaluated in other BC studies (all stages) using fixed-effect models. All statistical tests were 2-sided. Results: All heterogeneity of HR P values were > 0.20. OS, RFS, and DMFS in stage I-III BC pts were significantly worse for all gBRCAmut pts vs noncarriers; these outcomes were also significantly worse for gBRCA1mut-specific pts vs noncarriers (see table). Among other BC studies (all stages), nonsignificant OS was observed between gBRCAmut pts vs noncarriers. None of the studies reviewed provided outcomes-of-interest data specific to advanced BC and/or HR+/HER2- pts. Conclusions: In stage I-III BC studies, significantly worse OS, RFS, and DMFS were observed among gBRCAmut pts vs noncarriers. Our results support evaluation of gBRCAmut status in BC treatment, especially in earlier disease stages. Outcomes of Stage I-III BC studies* Outcome Type of gBRCAmut HR (95% CI) OS 1 1.64 (1.29-2.09) OS 1 or 2 1.90 (0.99-3.65) OS Combined 1.67 (1.33-2.10) RFS 1 3.03 (1.18-7.76) RFS 1 or 2 1.39 (0.74-2.58) RFS Combined 1.76 (1.05-2.95) DMFS 1 1.79 (1.10-2.91) DMFS 1 or 2 1.81 (1.03-3.17) DMFS Combined 1.80 (1.25-2.60) *No gBRCA2-specific stage I-III BC studies were available.
Anticipative monitoring to improve chemotherapy induced nausea.
Authors: Reza Elaidi, Stephane Oudard, Hail Aboudagga, Constance Thibault, Lorraine Waechter, Jerome Stevens, Brigitte Bonan, Florian Scotte
Journal: Journal of Clinical Oncology (2017)

10120 Background: The PROCHE [Programme for optimisation of the chemotherapy network] initiative is an innovative oncology-monitoring program designed to reduce patient waiting time and chemotherapy wastage, ultimately improving patient care. Methods: Primary objective was to evaluate the incidence of nausea reported by grade (NCI-CTC AE: from 0 to 4) from 2008 to 2016. Association was quantified using Mantel-Haenszel khi 2 and exact p-values. Secondary objective compared the 2009-2016 patients with the control patients of 2008 period. Results: Between Oct 2008 and Oct 2016, 3012 patients participated in the program, representing 36 803 questionnaires completed over the whole period. Nausea was, clinically and statistically, significantly improved during the whole follow-up period with a decrease of grade 3-4 from 0.6% to 0.08% and a decrease of grade 1-2 from 29.3% to 8.2%. The already adapted nausea management in 2008 with 70% of questionnaires reported no nausea improved to 92% in 2016, with a 10% improvement the year after program initiation. As MASCC propose to change guidelines with an improvement above 10%, such an organization may impact new recommendations. Conclusions: Anticipating anti-cancer treatment adaptation and prevention, following guidelines and using adapted antiemetics, explain these positive results. The PROCHE initiative improves chemotherapy induced nausea. [Table: see text]
Applying evidence-based software for NGS in pancreatic cancer: First results from the PePaCaKa study.
Authors: Matthias Loehr, Maximilian Kordes, Linnéa Malgerud, Sajo Kaduthanam, Jan Erik Frödin, Masoud Karimi, Jeffrey Yachnin, Carlos Fernandez Moro, Sam Ghazi, Rainer Lothar Heuchel, Valtteri Wirta, Carolin Hülsewig, Katrin Stecker, Marco Del Chiaro, Arne Ostman, Engstrand Lars, Stephan Brock, Maria Gustavsson-Liljefors
Journal: Journal of Clinical Oncology (2018)

e16214 Background: Pancreatic cancer (PDAC) is almost resistant to therapy, yet some patients profit from targeted therapy. We performed NGS on PDAC tissue and evidence-based, AI-supported evaluation to identify therapies based on biomarker profiles. Methods: After 1st line therapy, a 620-gene panel was used and data analysed with MH Guide software, a CE-marked medical device. Primary outcome was actionable mutations (drugable targets, effective or ineffective drugs, toxicity markers). Secondary outcome was change in therapy, overall survival, toxicity and adverse events. Results: 40 patients were enrolled, 35 tumors were analyzed and interpretable results were obtained from 31 patients. At least one significant biomarker was found in all cases. We found driver mutations in KRAS (n = 24), TP53 (n = 17), SMAD4 (n = 2), BRCA1/2 (n = 4; 3 germline), CDKN2A (n = 9), ATM (n = 6; 3 LOF), APC (n = 4), MSH3 (n = 15, 1 germline). Other mutations were in NOTCH2 (n = 19), MAP3K1 (n = 11), FANCD2 (n = 8). MH Guide made evidence-based recommendations in 30/31 patients: PARP-inhibitors (n = 26), MEK/RAF inhibitors (n = 20), CDK inhibitors (n = 9), other kinase inhibitors (n = 3), mTOR inhibitors (n = 2). The MTB decided on a recommended therapy in 26 cases, 2 patients received other 2nd line therapy and 2 BSC. Three patients died before and 2 during analysis, 1 died prior to the MTB, 2 died before start of therapy and 3 shortly after. Toxicity markers were found in 27/31 patients: Platinum (XRCC1 n = 16; 5 homozygous, TPMT n = 1; MUTYH n = 3), paclitaxel (CYP2C8 n = 2), gemcitabine (CDA n = 4; 1 homozygous) and 5-FU (DPYD n = 1), doxorubicin (G6PD n = 1), docetaxel (GSTP1 n = 2), sunitinib (ABCG2 n = 2), Irinotecan (ERCC2, n = 6; 5 homozygous, UGT1A1 n = 1). Roughly half of patients had adverse event CTCAE grade ≥3 during previous treatment independent of the presence of toxicity markers. 13/27 received chemotherapy for which they had a relevant toxicity marker, 7 had toxicity of any grade associable with the marker. Conclusions: Evidence-based personalized treatment recommendation in PDAC is feasible and can be implemented in a clinical setting. Common toxicity markers relevant for drugs used in PDAC could be detected but cannot be linked retrospectively to toxicity patterns. Clinical trial information: NCT02767700.
Expression quantitative trait loci (eQTLs) as germline determinants of melanoma immunotherapy response.
Authors: Robert Ferguson, Danny Simpson, Carlos N. Martinez, Matjaz Vogelsang, Esther Kazlow, Una Moran, Jeffrey S. Weber, Ryan J. Sullivan, Keith Flaherty, Anna C. Pavlick, Antoni Ribas, Iman Osman, Tomas Kirchhoff
Journal: Journal of Clinical Oncology (2017)

3017 Background: Approximately 40-60% of metastatic cutaneous melanoma (CM) patients do not respond to the current immunotherapy (IT) regimens, pointing to other yet unknown factors conferring IT resistance. Based on our recent findings showing that germline expression quantitative trait loci (eQTLs) in immune pathways associate with overall CM survival, in this study we tested whether germline immune-specific eQTLs also impact IT outcomes in CM. Methods: By interrogating a healthy twin cohort expression dataset (MuTHER), we have identified 50 eQTLs most significantly associated with the expression of 265 immune genes. Using the MassARRAY system, these 50 SNPs were genotyped in 138 anti-CTLA-4 treated patients, 59 PD-1 treated patients and 38 patients from combined (COMBO) treatments collected from multi-institutional collaborations. To test the association of SNPs with IT response, logistic regression was performed for each treatment group adjusting by demographic and clinical covariates. Results: We found significant associations with COMBO IT resistance for rs6673928 (OR = 4.249, p = 0.0167), an eQTL in IL10/IL19 which we have recently identified for association with melanoma survival; interestingly, it is a previously established locus associated with the risk of several autoimmune diseases. Additionally, we also identified eQTLs that are associated with IT sensitivity: rs4848306 in IL1-β with resistance to anti-CTLA-4 (OR = 0.373, p = 0.000733) and rs2071304 in SPI1with resistance to anti-PD-1 (OR = 0.3328, p = 0.0271). Conclusions: In this study we report that rs6673928, an eQTL from the IL19/IL10 locus previously shown to predict autoimmunity risk and CM survival, is also a surrogate marker of response to COMBO IT. The associations of rs6673928 with both IT response and CM survival indicate a strong relationship between interleukin pathways and the level of tumor immunogenicity. In addition to its apparent function in immune response, the putative multi-faceted role of this locus in predicting better survival and IT outcomes indicates high potential as a novel clinical target. Additional genetic and functional validation of these findings is currently underway in a large collaborative setting.
P04.13 LRIG3 and Soluble LRIG3 Ectodomain both inhibit the Proliferation and Invasion of Glioma cells in vitro and in vivo through modulation of Met-PI3K-Akt pathway
Authors: F Cheng, F Mao, Q Xiao, B Wang, D Guo
Journal: Neuro-Oncology (2018)

The human leucine-rich repeats and immunoglobulin-like domains (LRIG) gene family is a evolutionary conserved family comprising of LRIG1, 2, and 3, and encodes integral membrane proteins with an ectodomain, a transmembrane domain and a cytoplasmic tail. It is well documented that LRIG1 functions as a tumor suppressor in various types of cancer and LRIG2 may serve as a tumor promoter in glioma; however, although LRIG3 is low-expressed in many kinds of cancer, the function of it remains controversial. Moreover, the soluble ectodomains of LRIG1 and LRIG2 are demonstrated to be shed naturally and play similar roles to their corresponding full length proteins. Here we investigate whether the soluble ectodomain of LRIG3 (sLRIG3) is capable of being released from glioma cells and whether it has the similar founction as full-length LRIG3. Cells over-expressing LRIG3 were used to determine the existence of sLRIG3 in the conditional media. Full-length LRIG3 gene and the ectodomain LRIG3 gene were transduced into GL15 and U87 cells respectively, and LRIG3 siRNA was transduced into A172 cell. The proliferation rate, cell-circle assay, migration and invasion assay were all done to detect the founction of LRIG3 and sLRIG3. Soft-agar assay and subcutaneous tumor xenograft model in nude mice were carried out to determine the influence on tumorogenesis. Western blots were used to assertain the mechanism of these phenomena.The association of LRIG3 protein level and prognosis was performed using immunohistochemical(IHC) stain of paraffin sections of glioma tissues and survival analysis of 65 glioma patients. Also, the existence of sLRIG3 were detected through westernblot in patients’ body fluids. First, we found that low-expressed LRIG3 protein can be easily discovered in all glioblastoma cell lines.Then, we found sLRIG3 could be detected in the conditional media of the cells over-expressing LRIG3. Further research discovered that sLRIG3 has the same function as full-length LRIG3 on inhibiting cell proliferation, invasion and tumor progression, as well as in nude mouse subcutaneous tumor xenograft model. Mechanism research indicated that sLRIG3 inhibit Met-PI3K-Akt signaling pathway as full-length LRIG3. Moreover, the IHC stain of LRIG3 and survival analysis suggested LRIG3 to be an important clinical marker of prognosis in gliomas. We further confirmed the existence of sLRIG3 through western blot in patients’ plasma and tumor cystic liquids, but more precise method for quantitative detection is needed to confirm the relationship between sLRIG3 protein level and disease status. Our work reveals the existence of sLRIG3, which has the same tumor-supressing founctions as full-length LRIG3, and demonstrats that LRIG3 might represent as a promising new-diagnostic marker for gliomas and can be used as therapeutic agent.
Stratification of tumors based on mTOR-pathway biomarkers.
Authors: Jean-Francois Laes, S Bastien Sauvage, Gregori Ghitti
Journal: Journal of Clinical Oncology (2017)

e23097 Background: The mTOR pathway is often activated in human cancers. In this study, a total of 538 samples representing 40 different cancer types were analysed to evaluate the relationship between mTOR pathway activity and mutations in the upstream genes PIK3CA and PTEN. Methods: FFPE samples were analysed both by NGS (PIK3CA, PTEN, mTOR, TSC1, TSC2) and IHC (PTEN, 4pEBP1). Results: Overall, mTOR-pathway activation was identified in 83% of the samples, functional mutations were found in either or both PIK3CA and PTEN genes in 32% of the samples but there was no signification association between them. However when separating samples by cancer types, potential associations were identified. One example is the combination of PIK3CA activating mutation and PTEN loss of function which was associated with mTOR-pathway activation, most notably in the breast-cancer samples. Such combination has been associated with poor outcomes to some treatments (trastuzumab). Conclusions: In conclusion, our results show that stratification of tumors using the combination of mTOR-pathway biomarkers (and combined NGS and IHC technologies in their assessment) is potentially more informative than using a single biomarker to select the best treatment.
Post-operative concurrent chemo-radiotherapy versus post-operative radiotherapy in high-risk cutaneous squamous cell carcinoma of the head and neck: A randomized phase III trial (Trans Tasman Radiation Oncology Group 05.01 Trial; POST study).
Authors: Sandro Virgilio Porceddu, Michael Poulsen, Mathias Bressel, Adam Stoneley, Michael Veness, Lizbeth M. Kenny, Christopher Wratten, June Corry, Stephen Cooper, Gerald Fogarty, Marnie Collins, Michael Collins, Andrew Macann, Christopher Milross, Michael Gordon Penniment, Benedict Panizza, Danny Rischin
Journal: Journal of Clinical Oncology (2017)

6008 Background: We report on the first multi-centre randomized phase III trial of post-operative radiotherapy (PORT) vs post-operative chemo-RT (CRT) in high-risk cutaneous squamous cell carcinoma of the head and neck (cSCCHN) (NCT00193895). Methods: The primary objective was to determine whether there was a freedom from loco-regional relapse (FLRR) difference between patients randomly assigned to 60-66Gy (6-6.5 weeks) with or without weekly carboplatin (AUC 2) following resection of gross disease. Patients were stratified to high-risk nodal (either extracapsular nodal extension, intra-parotid nodal disease of any size or number, cervical nodal disease with ≥2 nodes or largest node &gt; 3cm) or high-risk primary (T3-T4 or in-transit metastases). Patients with both features were stratified to the high-risk nodal group. Secondary objectives included disease-free survival (DFS), overall survival (OS) and acute &amp; late toxicity (CTCAE V3). Results: 321 patients were randomly assigned between 2005-2014, with 11 not commencing treatment protocol due to disease progression or withdrawal of consent. Of the 310 patients commencing treatment protocol (157 RT and 153 CRT), 230 (74%) had high-risk nodal, 70 (22%) high-risk primary and 10 (3%) both. Median follow up was 60 months, median RT dose was 60Gy and 85% randomised to CRT completed 6 cycles of carboplatin. The 2- &amp; 5-year FLRR (95% CI) for the RT arm was 88% (83-93%)/83% (77-90%) and for CRT 89% (84-94%)/87% (81-93%) (HR 0.85; 95%CI [0.46-1.55]; p = 0.59). The 2- &amp; 5 year DFS (95% CI) for the RT arm was 78% (72-85%)/67% (60-76%) and for CRT 83% (77-89%)/73% (66-81%) (HR 0.85; 95%CI [0.55-1.29]; p = 0.43). The 2- &amp; 5 year OS (95% CI) for the RT arm was 88% (83-93%)/76% (69-84%) and for CRT 88% (83-94%)/79% (72-86%) (HR 0.95; 95%CI [0.58-1.57]; p = 0.84). 134 (43%) experienced Grade 3/4 skin toxicity; 49% RT, 37% CRT (p = 0.039). 12 (3.9%) experienced Grade 3/4 subcutaneous fibrosis; 2.5% RT, 5.2% CRT. Conclusions: While surgery and PORT provided excellent FLRR with acceptable toxicity, the addition of weekly carboplatin did not improve outcomes in high-risk cSCCHN. Clinical trial information: NCT00193895.
A phase 2 study to assess the efficacy and safety of autologous tumor-infiltrating lymphocytes (TIL, LN-145) alone and in combination with anti-PD-L1 inhibitor durvalumab in patients with locally advanced or metastatic NSCLC.
Authors: Sylvia Mina Lee, Missak Haigentz, Liza Cosca Villaruz, Igor Gorbatchevsky, Sam Suzuki, Susie Tanamly, Nancy Louise Samberg, Maria Fardis
Journal: Journal of Clinical Oncology (2018)

TPS3107 Background: Adoptive cell therapy with TIL has demonstrated durable complete responses in immunogenic tumors with high mutational burden. Durvalumab, which enhances T-cell antitumor cytotoxicity through blockade of the PD-1/PD-L1 axis, has demonstrated clinical activity in NSCLC. Despite recent advances in the treatment of NSCLC using checkpoint inhibitors, the majority of patients do not respond, leaving an unmet need to improve therapeutic outcomes, warranting this investigation of TIL therapy alone and in combination with durvalumab. IOV-LUN-201 is a phase 2 multicenter, open-label study designed to evaluate the efficacy and safety of autologous LN-145 therapy alone or in combination with durvalumab, for previously-treated, anti-PD-1/PD-L1-naïve NSCLC patients. Methods: LN-145 is a preparation of TIL extracted from surgically-resected tumors and manufactured in a 22-day process at a central GMP facility. LN-145 infusion is preceded by a non-myeloablative lymphodepletion regimen of cyclophosphamide and fludarabine, and followed by up to 6 infusions of IV IL-2. Cohort 1 patients receive LN-145 therapy alone. Patients in Cohort 1 who do not receive LN-145 or those who progress following LN-145 therapy can receive durvalumab 1500 mg IV Q4W until progression or unacceptable toxicity. Cohort 2 patients receive durvalumab 2 weeks prior to and 2 weeks after tumor harvest, and then following LN-145 infusion resume durvalumab 1500 mg IV Q4W until progression or unacceptable toxicity. Patients unable to receive LN-145 are allowed to receive durvalumab alone. Patients ≥ 18 years of age must have confirmed stage III/IV NSCLC and have received ≥1 line of prior systemic therapy, excluding anti-PD-1/anti-PD-L1. Other major eligibility criteria include: minimum of 2 tumor lesions, adequate organ function, and ECOG PS 0 or 1. Primary endpoints are efficacy as defined by ORR and safety of LN-145 as a single agent or in combination with durvalumab; secondary endpoints are DOR and PFS per RECIST 1.1, and OS. Key exploratory objectives include CR rate, DCR, immune correlates of response, and HRQoL. Clinical trial information: NCT03419559.