tbuckley/cabot-search huggingface dataset:
Tumor infiltrating lymphocytes (TILs) in HER2 positive breast cancer: Evaluation according to the new recommendations by the international TILs working group 2014.
Authors: Houman Nafisi, Jacques Raphael, Inna Y Gong, John M. S. Bartlett, Sunil Verma, Sharon Nofech-Mozes
Journal: Journal of Clinical Oncology (2015)

1037 Background: Assessment of TILS has gained interest in oncologic pathology especially as a predictor of outcome in HER2+ and triple negative breast cancer (BC). Recently, a standardized approach to assess TILs on routine histopathology slides as a biomarker in BC was recommended by an international panel of experts. Using this approach, we assessed the inter rater reliability and predictive value of TILs in HER2+ locally advanced BC cases. Methods: Core biopsies from52 HER2+ BC patients obtained prior to neoadjuvant (NAT) chemotherapy with or without trastuzumab (T) were identified. Two pathologists independently quantified stromal TILs, intratumoral heterogeneity (ITH), presence of lymphocyte predominant (LPBC, ≥ 60%) BC and tertiary lymphoid structure (TLS) using H&E-stained slides following 2014 international guidelines. Discordant results were resolved by reviewing on a double headed microscope. The association of TILs as continous and categorical (LPBC) variables with complete pathological response (pCR) rates was determined by Mann-Whitney WIlcox test. Inter rater reliability was measured using Cohen’s Kappa coefficient. Results: An average of 4 cores per case were assessed. 8/52 (15%) cases had LPBC. Heterogeneity was mild in 30, moderate in 16 and severe in 6 cases. The pathologists agreed on 90%, 96% and 88% of the cases for quantitative TILs, LPBC( ≥ 60%) and ITH, inter rater reliability was excellent (Cohen’s Kappa 0.89, 0.85 and 0.81 respectively). On univariate analysis, high levels of TILs and LPBC were associated with greater pCR rates for the cohort of patients who received NAT with T (p= 0.004, p = 0.05 respectively). Conclusions: Our results show that the levels of TILs can be reliably assessed on breast core biopsies. High levels of TILs as a continous variable and LPBC are candidate predictors of pCR in Her2+ BC patients receiving NAT T.
Use of exon-based transcriptome profiling to identify novel signaling pathways and survival-associated genes in diffuse large B-cell lymphoma.
Authors: Sirpa Leppa, Minna Taskinen, Satu Koivula, Ping Chen, Riku Louhimo, Jan Delabie, Marja-Liisa Karjalainen-Lindsberg, Magnus Bjorkholm, Oystein Fluge, Lars Moeller Pedersen, Karin Rydstrom, Mats Jerkeman, Mikael Eriksson, Sampsa Hautaniemi, Harald Holte
Journal: Journal of Clinical Oncology (2012)

8074 Background: Identification of biological prognostic factors that could be used to define poor risk diffuse large B-cell lymphoma (DLBCL) patients is a main concern. Methods: Study population consisted of 38 de novo high risk DLBCL patients less than 65 years old. The patients were treated in the Nordic phase II protocol with six courses of R-CHOEP14 followed by systemic central nervous system prophylaxis with one course of high dose methotrexate and one course of high dose cytarabine. Exon array-based profiling was used to screen signaling pathways and differentially expressed genes between the clinically high risk patients, who had relapsed or remained in remission in response to dose dense chemoimmunotherapy. At the time of the analysis, median follow up was 34 months, progression free survival (PFS) 78% and overall survival (OS) 78%. Results: The screen between relapsed patients and the patients in remission using criteria of p ≤ 0.05 and fold change ≥ 1.6 revealed 566 differentially expressed genes (131 protein coding), of which 24 were likely to be involved in conventional signaling pathways, including those regulating antigen processing and presentation (CIITA, HLA-DQA2, HLA-DQB1, RFXAP), Jak-STAT signaling (SOCS3), Notch signaling (NOTCH1) and Toll-like receptor signalling (IRF5). In cox univariate analysis, 12 of 24 genes were found to associate with PFS (p&lt;0.05). Of these, high expression of CIITA, DLL4, HLA-DQA2, HLA-DQB1, IRF5, NOTCH1, PER1, RFXAP, SEMA4D and ZFP36 had a favorable impact on PFS, whereas high levels of ENPP3 and PRKAR2B were associated with adverse outcome. Differential expression of four genes was confirmed by quantitative PCR, and prognostic value of six genes validated using Lymphoma/Leukemia Molecular Profiling Project microarray data set. Immunohistochemical validation of the findings in a larger patient cohort is ongoing. Germinal centre B-cell signature did not predict survival in this cohort. Conclusions: The results provide evidence that exon-based transcriptome profiling can identify biologically relevant signaling pathways and genes that discriminate the outcome of homogenously treated young high risk DLBCL patients.
Primary tumor resection to improve survival in patients with metastatic colorectal cancer in the post-2000 era: A California Cancer Registry analysis.
Authors: Ana Milena Rodriguez Fahrni, I-Yeh Gong, Rosemary Cress, Yingjia Chen, Thomas John Semrad, Vijay P. Khatri
Journal: Journal of Clinical Oncology (2013)

e14570 Background: Resection of primary tumors in the setting of metastatic colorectal cancer (MCRC) is controversial. Fewer primary tumor resections are being performed due to the improved tumor responses and disease control rates associated with modern systemic therapy. Recent studies suggest a survival benefit for patients with MCRC who had primary tumors resection prior to systemic therapy. This analysis evaluates the independent prognostic impact of primary tumor resection on overall survival (OS) for patients with MCRC using the California Cancer Registry (CCR). Methods: We queried the CCR for all patients with MCRC diagnosed between 2003 and 2010. Patients were categorized by whether or not they had primary tumor resection at time of diagnosis. Covariates included gender, age, race/ethnicity, socioeconomic status (SES), and rural-urban commuting area (RUCA) score of patients. Univariate comparisons were made using the Kaplan Meier method. Multivariate comparisons were performed using the Cox proportional hazards regression method. Results: 19,836 patients met the criteria for analysis of whom 11,566 (58%) had primary tumor resection. Primary tumor resection rates declined over this time period (63% in 2003 v. 52.8% in 2010, p&lt;0.0001), varied by SES (55% v. 62%: lowest versus highest, p&lt;0.001) and residence (63% in rural versus 58% for urban, P=0.0160). On multivariate analysis, overall survival was significantly better for patients that had primary tumor resection (HR: 0.467 [95% CI: 0.467-0.482]; p&lt;0.0001). Survival was statistically longer in younger patients (HR: 1.385 for age 65-75, HR: 2.217 if greater than age 75), highest SES (HR: 0.869, p&lt;0.0001), Hispanics (HR: 0.884, p&lt;0001), and Asian/Pacific Islanders (HR:0.892, p&lt;0.0001). Overall survival was worse for African Africans (HR:1.105, P=0.0001). Conclusions: Our study demonstrates the independent prognostic value on survival of primary tumor resection in patients with MCRC. There is significant variability of resection rates by SES and rural-urban residence. As analysis of CCR data cannot eliminate the influence of patient and provider biases, a prospective randomized trial is warranted.
Impact on pathologic complete response with long-course or hypo fractionated preoperative radiotherapy in combination with chemotherapy in rectal cancer.
Authors: Dr. Consuelo Diaz, German Caderillo-Ruiz, MaryTere Herrera, Erika B. Ruiz Garcia, Itzel Vela Sarmiento, Horacio Noe López-Basave, Alejandro Padilla, Manuel Flores Castro, Alejandro Mohar, Jose Luis Aguilar
Journal: Journal of Clinical Oncology (2015)

e14701 Background: Chemoradiotherapy neoadjuvant is standard treatment in Locally Advanced Rectal Cancer (LARC). Two schemes of preoperative radiotherapy: long course (45–50.4Gy/25fr) and short course (25Gy/5fr) both are effective in tumor control; different chemotherapeutic agents concomitant improving local control. We assess tumoral response in patients who underwent preoperative radiotherapy with two different protocols: long course of 45Gy/25 fractions and hypofractionated (45Gy/15fr) concomitant with capecitabine or 5-fluorouracil (5-FU). Methods: A total of 135 patients with LARC, received treatment preoperative(2005 - 2012) were analyzed pathological response.75(n) treated with hypofractionated 45Gy/15 fr in fifteen days and 60 received radiotherapy (45Gy/25fr), simultaneous treatment with 5-FU, leucovorin intravenous or capecitabine 850mg/m2twice a day for fourteen days. Pathological Complete Response (pCR) including downstaging tumour (T)/nodal (N) after surgery. Results: 135 patients were analized,mean age 53 years,58 female and 77 men. 64 (48%) patients were treated with 5-FU and 71 (52.5%) with capecitabine, four cycles of chemotherapy was mean of treatment. Tumoral pathological complete response was in 31 (22%) of all patients, 14% vs 9% of the patients treated with hypofractionated and conventionally radiotherapy, the difference was not significant (p = 0.46). A pCR was shown in 13 patients of 5-FU with hypofractionated radiotherapy and 2 patients who received conventional radiotherapy. In the capecitabine group 6 of 31 patients with hypofractionated and 10 of long course had a pCR. There was no significant difference in of pathologic complete response between patients who received capecitabine vs 5-FU (pCR: 12.8% vs. 11.1%; p = 0.93). Conclusions: Preoperative short term radiotherapy and long courses provide local control in rectal cancer; with this retrospective results are according to literature than short-course irradiation it is same effective of long-course in the pathological tumor response. Is necessary prospective study for data on survival and relapse in our population.
Long-term survival of patients with metastatic melanoma (MM) treated with dacarbazine (DTIC) or temozolomide (TMZ)
Authors: C. Kim, C. W. Lee, R. Klasa, A. Shah, K. J. Savage
Journal: Journal of Clinical Oncology (2009)

9054 Background: Patients with metastatic melanoma (MM) generally have a poor prognosis, with a median survival of 6 to 9 months. There is a small proportion of patients who achieve long term survival (LTS), however, it is unclear whether LTS reflects sensitivity to systemic therapy, indolent tumor biology or host immune factors. Dacarbazine (DTIC) is the only approved chemotherapy for the treatment of MM, although temozolomide (TMZ) has similar efficacy. There is limited information as to the frequency of complete response (CR) following DTIC or TMZ, duration of response and whether LTS occurs only in patients who achieve a CR. We sought to identify all patients with MM treated with either DTIC (alone or in combinations) or TMZ at the BC Cancer Agency (BCCA) who achieved LTS defined as survival ≥ 18 months from the time of administration of chemotherapy. Methods: All patients with MM treated with either DTIC or TMZ from January 1, 1988 to February 1, 2006 were identified in the BCCA pharmacy database. The BCCA surveillance and outcomes unit (SAO) was utilized to identify cases of LTS. CR was defined as disappearance of all disease by diagnostic imaging. Given the retrospective nature of the analysis, progressive disease (PD) was defined as any tumor growth, and partial response or stable disease (PR/SD) were combined. Results: In the 18-year period reviewed, 397 patients with MM were treated with DTIC (n= 349) or TMZ (n=48). Of these, 45 patients met the criterion of LTS and had the following characteristics: median age 53 (range 22–86); male 67 %; ocular primary 7%; non-pulmonary visceral metastases 38%; DTIC 11.7% (41/349), TMZ 8.3% (4/48). The best response to DTIC or TMZ documented was: CR 18%, PR/SD 67%, PD 13%. The 5-year overall and progression-free survival rates were 33% and 12%, respectively. Eleven patients survived &gt; 5 years (range 5–27.5), and 6 patients remain in remission (5 CR, 1 PR). Disease progression occurred in 5 patients in &lt; 1 year however, they remain alive for at least 5 years (range 5.2–17.9). Conclusions: LTS occurs in patients with MM treated with either DTIC or TMZ. However, a minority have a sustained response following chemotherapy, and most cases of LTS are likely the result of indolent disease or host biology. No significant financial relationships to disclose.
Compliance and efficacy of induction chemotherapy with cisplatin, docetaxel, and fluorouracil followed by radiotherapy plus cisplatin or cetuximab for locally advanced oropharyngeal tumours.
Authors: Carine Fuchsmann, Jerome Fayette, Sophie Tartas, Veronique Favrel, Pascal Pommier, Philippe Zrounba, Antoine Ramade, Severine Racadot, Marc Poupart, Philippe Ceruse
Journal: Journal of Clinical Oncology (2013)

e17012 Background: This study aimed to assess compliance and survival after induction chemotherapy (IC) with docetaxel, cisplatin, fluorouracil (DCF) followed by radiotherapy plus cisplatin (RTCis) or radiotherapy plus cetuximab (RTCet) in a retrospective multicentric series of 121 patients with locally advanced oropharyngeal cancer. One of the issues of these chemotherapy regimens is the toxicity that adversely affects the compliance to the concomitant radiochemotherapy treatment. We also evaluated feasibility and completion of radiochemotherapy treatment comparing efficacy and toxicity between RTCet and RTCis. Methods: Multicentric retrospective review of 121 consecutive patients with non resectable or non operable oropharyngeal carcinomas treated between 2005 and 2011 in 3 tertiary care centers with protocol ongoing in each center. In one center DCF, is followed by RTCet, in the 2 other centers, DCF is followed by RTCis. Primary endpoints were acute toxicity of IC and compliance to the RTCis compared with RTCet. Secondary endpoints were overall survival, disease free survival and locoregional control. Results: Within the 121 patients, 20.7% were stage III and 79.3% were stage IV. 81.8% of the patients completed the full course of IC. 50% of the patients had full dose concomitant cisplatin versus 77% of the patients that had full dose concomitant cetuximab (p=0.017). Mean follow up was 23.5 months. Median overal survival was 20.7 months, median disease free survival was 18.6 months. The 3 and 5 year overall survival rates were respectively 52.5% and 46.4%. The 3 and 5 year disease free survival rates were 44.2% and 38.3%. The only significant factor affecting survival was IC response (p&lt;0.05). No statistically significant difference in survival was found between patients with concomitant cisplatin or cetuximab. Conclusions: Induction chemotherapy with DCF followed by RTCis or RTCet allowed good survival rates with acceptable toxicities. Cetuximab seemed to be better tolerated than cisplatin improving compliance to the treatment.
Effect of BIM and mTOR expression on clinical outcome to erlotinib in EGFR-mutant non-small cell lung cancer (NSCLC) patients (p).
Authors: Niki Karachaliou, Ana Drozdowskyj, Ana Gimenez Capitan, Andres Felipe Cardona Zorrilla, Radj Gervais, Bartomeu Massuti, Teresa Moran, Margarita Majem, Enriqueta Felip, Enric Carcereny Costa, Rosario Garcia Campelo, Santiago Viteri Ramirez, Daniela Morales-Espinosa, Alberto Verlicchi, Elisabetta Crisetti, Imane Chaib, Jose Luis Ramirez, Patrick C. Ma, Rafael Rosell
Journal: Journal of Clinical Oncology (2014)

8072 Background: Sixty percent of EGFR-mutant NSCLC p respond to erlotinib, but overall survival (OS) is the same for upfront chemotherapy. Priming BIM, a pro-apoptotic signaling BH3-only protein, induced sensitivity to erlotinib in EGFR-mutant cell lines (Costa el at. PLoS Med 2007). BIM was related to response and progression-free survival (PFS) in clinical tumor samples, but OS was not reported (Faber et al. Cancer Disc 2011). Mammalian target of rapamycin (mTOR) negatively regulates apoptosis and could influence response to erlotinib. Methods: We assessed static levels of total BIM, BIM-extra long (BIM-EL – a main isoform of BIM), and mTOR mRNA expression and correlated findings with response and OS in 57 erlotinib- or chemotherapy-treated EGFR-mutant NSCLC p in the EURTAC trial. Results: Median age 65; 70.2% female; 59.6% never-smokers; 91.2% adenocarcinoma. Response rate 88.9% for erlotinib-treated p with high total BIM levels, compared to 22.2% with low/intermediate total BIM levels (P=0.0027). Sensitivity/specificity of total BIM as a predictor of response to erlotinib was highly significant (AUC=0.80; P=0.0056). OS was 35.8 months (m) for p with high and 17.7 m with low/intermediate total BIM (P=0.023). Notably, among p with high total BIM, OS was 35.8 m for p with low/intermediate mTOR levels, compared to 20.3 m with high mTOR levels (P=0.4848). In contrast, mTOR did not affect OS in p with low/intermediate BIM (17.5 m vs 25.1 m; P=0.9498). BIM-EL assessment was only possible in 31 p, due to insufficient tumor sample in the remaining p. However, in this subset, BIM-EL seemed to have greater predictive power than total BIM. Conclusions: Our findings highlight the potential usefulness of BIM mRNA as a predictive biomarker of response in EGFR-mutant NSCLC p. Those with low BIM expression could derive only meager benefit from treatment with EGFR TKIs alone but could benefit from synthetic lethality combinations, including BcL-2 inhibitors. Those with high BIM expression could benefit from erlotinib or similar EGFR TKIs, but analysis of mTOR could further improve outcome by selecting p with high mTOR for combination therapy with EGFR TKIs and mTOR inhibitors.
Regorafenib treatment for advanced, refractory gastrointestinal stromal tumor: A report of the U.K. Managed Access Program.
Authors: Marco Maruzzo, Attila Kollar, Charlotte Benson, Christina Messiou, Elizabeth Cartwright, Beatrice M. Seddon, Palma Dileo, Aisha Miah, Juan Martin-Liberal, Khin Thway, Ellen McGrath, Alison Dunlop, Ian Robert Judson, Mark David Linch
Journal: Journal of Clinical Oncology (2014)

10551 Background: Tyrosine kinase inhibitors (TKI) have revolutionized the treatment of gastrointestinal stromal tumours (GIST) although most patients develop resistance to first and second-line therapies. Regorafenib, an oral multi-targeted TKI, has demonstrated benefit in previously treated GIST patients. Methods: We assessed safety and preliminary activity of regorafenib in patients treated within the Managed Access Programme (MAP). All consecutive patients with advanced GIST who had progressed on or were intolerant of imatinib and sunitinib were recruited from the Royal Marsden Hospital and University College Hospital. We retrospectively reviewed the data for response, toxicity and treatment duration. Response was assessed by RECIST and Choi criteria. Toxicity was graded according to CTCAE v4.0 criteria. Results: 20 patients were included in the MAP in the UK between 3/2013 and 9/2013. Median age was 68 (range 45-87), 65% of patients were male. Performance Status was 0-1 for 18 patients (90%), 2 for 2 patients (10%). The median treatment duration was 29 weeks (range 1-50). 18 patients were assessable for response and all patients attained a best response of at least stable disease. At a median follow-up of 6.7 months, there were 2 partial responses (11%) by RECIST and 7 partial responses (39%) according to Choi’s criteria. One patient who had a PR on regorafenib had not benefited from previous sunitinib. 3 patients had disease progression and 3 patients discontinued treatment due to unacceptable toxicities; fistulation, myalgia and fatigue. 10 (50%) patients had grade 3 toxicities and 11 (55%) patients required a dose reduction. 5 patients started at reduced dose due to previous significant TKI toxicity, however 2 patients were able to be dose escalated. Median PFS and OS have not yet been reached but notably, prolonged stable disease was seen in 1 patient with exon 9 mutation and 1 patient with PDGFR D842V mutation. Conclusions: These data demonstrate encouraging activity of regorafenib in routine clinical practice. The documented adverse events are in line with previous trial data. Updated survival data and the role of RECIST/Choi response criteria in predicting survival will be presented.
Frequency and clinical characterization of NSCLC patients harboring PIK3CA mutations identified within a regional screening network.
Authors: Masyar Gardizi, Matthias Scheffler, Lukas Carl Heukamp, Marc Christiaan Allardt Bos, Kerstin Albus, Birgit Hayn, Yon-Dschun Ko, Andreas Schlesinger, Michael Brockmann, Monika Heidi Serke, Ulrich Gerigk, Khosro Hekmat, Erich Stoelben, Marcel Reiser, Roland Schnell, Stephan H. Schmitz, Konrad Frank, Reinhard Buettner, Jurgen Wolf, Thomas Zander
Journal: Journal of Clinical Oncology (2012)

10526 Background: PIK3CA mutations are a rare oncogenic event of potential therapeutic relevance in NSCLC. Here we report frequency and characteristics of patients with PIK3CA mutated lung tumors. Methods: Patients with NSCLC and PIK3CA mutations were identified within our regional Network for Molecular Screening in Lung Cancer. We further analyzed the presence of BRAF, KRAS, EGFR mutations as well as ALK translocation, ERBB2 and FGFR1 amplifications in PIK3CA mutated samples. Clinical data on age, sex, TNM classification and tumor stage, histological type, grading, overall survival, smoking status, comorbidity, BMI and secondary malignancies were retrieved from clinical charts in accordance with the local ethics committee. Results: PIK3CA mutations were detected with a frequency of 3.7% (24% exon 20,76% exon 9) in 1000 patients. Histologically 32% were defined as squamous cell carcinoma, 48% as adenocarcinoma and 18% other histological subtypes or NSCLC-NOS. Exon 9 mutations were present in the acinar and lepidic subtype, whereas exon 20 mutations were seen in the papillary and solid subtype. Cooccuring genetic lesions were observed in 16% (mutations in KRAS=2, EGFR=1, BRAF=1; FGFR1 amplification=2). 14 were female, 23 male with a mean age of 69 years. 21 of these patients were further clinically annotated. 11 patients presented with stage IIIb/IV eligible for palliative treatment and 10 stage I – IIIa eligible for surgical therapy +/- adjuvant therapy. All but 1 patient were smokers with an average BMI of 26,2kg/m2 with a typical high load of comorbidity mainly of cardiovascular diseases, 8 of 21 patients showed prior malignancies in their medical history. The median overall survival within this population has not been reached yet. Conclusions: Screening for PIK3CA mutations is feasible. A high proportion (38%) of patients with PIK3CA mutated lung cancer have prior malignancies and show a high load of comorbidity. Furthermore PIK3CA mutations are not exclusive to KRAS, EGFR or BRAF mutations or FGFR1 amplifications. Successful identification of patients with oncogenic lesions in lung cancer in a screening network might allow future personalized treatment of these patients.