tbuckley/cabot-search huggingface dataset:
Pertuzumab + trastuzumab for HER2-amplified/overexpressed metastatic colorectal cancer (mCRC): Interim data from MyPathway.
Authors: Herbert Hurwitz, Kanwal Pratap Singh Raghav, Howard A. Burris, Razelle Kurzrock, Christopher Sweeney, Funda Meric-Bernstam, Ari M. Vanderwalde, David R. Spigel, Ron Bose, Marwan Fakih, Charles Swanton, Shuangli Guo, Coen Bernaards, Mary Stanley Beattie, Nicolas Sommer, John D. Hainsworth
Journal: Journal of Clinical Oncology (2017)

676 Background: Among recent advances in precision medicine, HER2 has emerged as a potential therapeutic target for advanced colon cancer. MyPathway is a multi-basket study evaluating the efficacy and safety of targeted therapies in non-indicated tumor types harboring relevant genetic alterations. We present updated data for an expanded cohort of patients with HER2-amplified/overexpressed mCRC receiving HER2-targeted therapy with pertuzumab + trastuzumab. Methods: MyPathway (NCT02091141) is a multicenter, open-label, phase IIA study. Patients in this analysis had treatment-refractory HER2-amplified/overexpressed mCRC by gene sequencing, FISH, or IHC. Patients received standard doses of pertuzumab + trastuzumab until disease progression or unacceptable toxicity. The primary endpoint is investigator-assessed overall response rate. The cutoff date was July 31, 2016. Results: Of 34 patients with mCRC enrolled, 32 have had ≥1 tumor assessment. At a median follow-up of 5.2 (range 0.7–18.3) months from treatment initiation, 12 patients had partial responses (PR), with stable disease (SD) for &gt;4 months in 3 additional patients (Table). The safety profiles were consistent with the product labels. Conclusions: Interim data show that HER2-targeted therapy with pertuzumab + trastuzumab, a chemotherapy-free regimen, is active in heavily pretreated HER2-amplified/overexpressed mCRC. The ORR was 37.5%, responses were durable (median 11.1 months), and the CBR was 46.9%. Accrual to MyPathway is ongoing. Clinical trial information: NCT02091141. [Table: see text]
Baseline creatinine clearance as an indicator of severe adverse events associated with oxaliplatin-based adjuvant chemotherapy in patients with stage III colon cancer: Safety analysis of the phase III Japanese ACHIEVE trial.
Authors: Masato Nakamura, Masahito Kotaka, Tetsuya Eto, Dai Manaka, Junichi Hasegawa, Akinori Takagane, Takeshi Kato, Yoshinori Munemoto, Fumitaka Nakamura, Hiroyuki Bando, Hiroki Taniguchi, Makio Gamoh, Manabu Shiozawa, Takeharu Yamanaka, Tsunekazu Mizushima, Junichi Sakamoto, Shigetoyo Saji, Atsushi Ohtsu, Masaki Mori, Takayuki Yoshino
Journal: Journal of Clinical Oncology (2017)

667 Background: The phase III ACHIEVE trial (JFMC47), a project of the International Duration Evaluation of Adjuvant Chemotherapy (IDEA), was established to prospectively analyze data from several randomized trials to test whether 3-month (arm 3) oxaliplatin-based adjuvant (FOLFOX4, mFOLFOX6, or XELOX) treatment is non-inferior to 6-month (arm 6) treatment in terms of disease-free survival in patients (pts) with stage III colon cancer. It aims to reveal the association between baseline characteristics and ≥ grade 3 adverse events (AEs) related to XELOX and mFOLFOX6, particularly focusing on the role of baseline creatinine clearance (CCr) on ≥ grade 3 AEs. Methods: This association was assessed using the Cox proportional hazards model. Results: During 2012–2014, 1,313 pts were randomized from 244 centers; 1,301 were included in the intention-to-treat population. Among the safety population (N = 1,277; 642, arm 3; 635, arm 6), the overall incidence of ≥ grade 3 AEs was 29% in arm 3 and 43% in arm 6 (p &lt; 0.0001). Neuropathy of ≥ grade 2 was more frequent in arm 6 than in arm 3 (37% vs. 14%; p &lt; 0.0001). Regarding the fluoropyrimidine backbone, grade 3–4 neutropenia was more with mFOLFOX6 than XELOX (30% vs. 12%), whereas grade 3–4 anorexia (2% vs. 5%) and grade 3–4 diarrhea (1% vs. 6%) were more with XELOX. Multivariate analysis, including treatment duration, regimen, CCr ( &lt; 50 vs. &gt; 50 mL/min), age, and sex, showed that CCr had a statistically significant impact on the occurrence of ≥ grade 3 AEs (hazard ratio = 0.44, p &lt; 0.0001). Pts with CCr &lt; 50 may have had more frequent ≥ grade 3 AEs independent of other factors, such as age. Conclusions: Grade 3 or higher AEs related to XELOX or mFOLFOX6 may be associated with the degree of CCr. Clinical trial information: UMIN 000008543.
Postoperative follow-up of lung cancer: Randomized trial comparing two follow-up programs in completely resected non-small cell lung cancer (IFCT-0302).
Authors: Virginie Westeel, Fabrice Barlesi, Jean Domas, Philippe Girard, Pascal Foucher, Jean-Jacques Lafitte, Patrick Dumont, Marie Wislez, Elisabeth A. Quoix, Denis Braun, Marie Paule Lebitasy, Jacques Hermann, Marc Derollez, Gervais Ozenne, Olivier Raffy, Etienne Devin, Hubert Barbieux, Jean Tredaniel, Franck Morin, Didier Debieuvre
Journal: Journal of Clinical Oncology (2012)

TPS7111 Background: There are no robust data published on the follow-up after surgery for non-small cell lung cancer (NSCLC). Current international guidelines are informed by expert opinion. Most of them recommend regular follow-up with clinic visit and thoracic imaging, either chest X-ray of Chest CT-scan. The IFCT-0302 trial addresses the question whether a surveillance program with chest CT-scan and fiberoptic bronchoscopy can improve survival compared to a follow-up only based on physical examination and chest x-ray. There is no such trial ongoing over the world. Methods: The IFCT-0302 trial is a multicenter open-label controlled randomized phase III trial. The objective of the trial is to compare two follow-up programs after surgery for stage I-IIIa NSCLC. The primary endpoint is overall survival. Patients are randomly assigned to arm 1, minimal follow-up, including physical examination and chest x-ray; or arm 2, a follow-up consisting of physical examination and chest x-ray plus chest CT scan and fiberoptic bronchoscopy (optional for adenocarcinomas). In both arms, follow-up procedures are performed every 6 months during the first two postoperative years, and every year between the third and the fifth years. The main eligibility criteria include: completely resected stage I-IIIA (6th UICC TNM classification) or T4 (in case of nodules in the same lobe as the tumor) N0 M0 NSCLC, surgery within the previous 8 weeks. Patients who have received and/or who will receive pre/post-operative chemotherapy and/or radiotherapy are eligible. Statistical considerations: 1,744 patients is required. Accrual status: 1,568 patients from 119 French centers had been included. The end of accrual can be expected for September 2012. Ancillary study: Blood samples are collected in 1000 patients for genomic high density SNP micro-array analysis. This collection will contribute to the French genome wide association study (gwas) of lung cancer gene susceptibility, and the genetic factors predictive of survival and lung cancer recurrence will be analyzed.
Final pre-specified analysis of the phase II trial of the AE37+GM-CSF vaccine in high risk breast cancer patients to prevent recurrence.
Authors: Julia M. Greene, Erika J Schneble, Jonathan Martin, Madeline Flores, John S. Berry, Alfred F. Trappey, Timothy J. Vreeland, Diane F. Hale, Alan K. Sears, Guy T. Clifton, Eric von Hofe, James Thomas Symanowski, Alexandros Ardavanis, Nathan M. Shumway, Sathibalan Ponniah, Michael Papamichail, Sonia A. Perez, George Earl Peoples, Elizabeth Ann Mittendorf
Journal: Journal of Clinical Oncology (2015)

622 Background: We are conducting a Phase II clinical trial of the AE37+GM-CSF vaccine for the prevention of breast cancer recurrence in disease-free, node-positive or high-risk node negative patients (pts). AE37, is an MHC Class II epitope capable of stimulating CD4+ helper T cells. Here, we present the final pre-specified analysis of the primary endpoint of disease free survival (DFS) at one year from last enrolled pt. Methods: After completion of standard of care therapy, pts with any level of HER2 expression (IHC1-3+) were randomized to the vaccine group (VG) to receive 6 monthly intradermal inoculations of AE37+GM-CSF followed by 4 booster vaccinations every 6 months, or to receive GM-CSF alone on the same schedule as a control group(CG). Demographic, safety, immunologic, and clinical recurrence data are being collected. DFS is compared using Kaplan-Meir methods (5 yr DFS rates and logrank test) and Cox proportional hazards models (HR estimates with 95% CI). Continuous variables are compared using analysis of variance techniques and proportions compared with Fisher’s exact test. Results: Of 301 enrolled pts, 154 were randomized to the VG and 147 to the CG. There were no differences in age, grade, receptor status, tumor size or nodal status between groups (all p ≥ 0.1). Five-year DFS rates were not different with 82% (VG) vs 79.9% (CG), HR = 0.96, p = 0.9. There were trends in several subgroups. In HER2 1-2+ pts (77 VG vs 80 CG), 5 yr DFS was 79% (VG) vs 75% (CG), HR 0.76, p = 0.48. In ER/PR- pts (59 VG vs 56 CG), 5 yr DFS was 83% (VG) vs 77% (CG), HR 0.67, p = 0.36. In TNBC pts (25 VG vs 26 CG), 5 yr DFS was 67% (VG) vs 62% (CG), HR 0.65, p = 0.42. Conclusions: Overall, the final timed analysis of this phase II trial shows no statistical differences between treatment arms; however, it does identify particular pt populations where the vaccine may have efficacy. The ER/PR negative and triple negative pts appear to derive greatest benefit from AE37 vaccination with reductions in relative risk of recurrence of 33% and 35%, respectively. Further studies are required to confirm these findings and investigate the link between hormone receptor status and induction of clinically beneficial anti-tumor immunity by the AE37 vaccine. Clinical trial information: NCT00524277.
Identification of the activated form of the estrogen receptor (ER) in breast cancer (BC).
Authors: Erard M. Gilles, Jacques Bosq, Suzanne A.W. Fuqua, Alexander A. Zukiwski, Jean-Michel Caillaud, Barthelemy Gilles, Jacques Bonneterre
Journal: Journal of Clinical Oncology (2013)

e11535 Background: : About 50% of ER positive (ER pos ) BC are resistant to hormone treatment. In absence of ligand, ERs are evenly distributed in nuclei in normal tissue. Upon ligand binding, ERs dimerizes and form a discrete focal subnuclear distribution pattern (FDP), which are associated with transcriptional activation of ER. This ER FDP is observed in BC. We hypothesized that in BC that the presence/absence of ER in the FDP could predict antiestrogen activity. This study describes an immunohistochemistry (IHC) method, by which a biomarker could be developed to investigate this hypothesis. Methods: 37 paraffin embedded, formalin fixed archived BC samples were processed using 4 ER-alpha antibodies (Ab) under different IHC conditions to develop and refine this biomarker, the ER nuclear morphology was analyzed with standard microscopy at x1000. Interpretation of the IHC slides was done by an experienced pathologist. Standard ER, progesterone receptor (PR), and Ki67 testing were done. Tumor grade was obtained from the patients’ records. Analysis of the different Ab was with the kappa statistics. Comparison of the IHC technique to immunofluorescence (IHF) was done on 8 samples. Results: Consistent with prior research observations, tumors had two ER nuclear morphologies: 1. Diffuse pattern (D) where the ER was distributed evenly in a fine granular pattern, 2. Aggregate pattern (A) where the ER is distributed in distinct clumps or aggregates. This defined 3 tumor phenotypes: A cells only (A) 1% (4/37), D cells only (D) 65% (24/37), and a heterogenous mix of A + D cells (AD) 18% (7/37), ER Neg 14% (5/37). IHC and IHF analysis for ER nuclear morphology was concordant. The ER activation status (A/AD or D) was not correlated with staining ER intensity, ER pos %, PR pos %, but was correlated with % Ki67 staining (p=0.09) and tumor grade (0.035). Conclusions: ER pos early BC biopsies can be grouped in two categories based on ER nuclear morphology: A group with diffuse and homogenous nuclear staining, and a different group with heterogeneous area of cells having a nuclear pattern consistent with a functional or activated ER. These observations warrant clinical pathological studies to determine if this biomarker is potentially predictive of clinical outcomes.
A short-term neoadjuvant pilot study comparing exemestane and letrozole in postmenopausal women with estrogen receptor-positive HER2-negative breast cancer.
Authors: Daishu Miura, Tsuguo Iwatani, Hidetaka Kawabata
Journal: Journal of Clinical Oncology (2012)

591 Background: Current approaches of neoadjuvant endocrine therapy (NAET) are focusing on biomarker analysis of the diagnostic specimens. One of the important things in neoadjuvant treatment is to determine the in-vivo responsiveness to the agent. Little is known regarding biomarker changes in specific agents and the association with biomarker changes and treatment duration. A pilot study was conducted to investigate the differences of biomarker changes in short-term NAET (letrozole vs. exemestane) and also the difference in treatment durations of each AI. Methods: Totally 120 samples from 60 postmenopausal women with ER positive HER2 negative stage 1-3 breast cancers in NAET comparing letrozole (LET) and exemestane (EXE) were analyzed with pre- and post-treatment mRNA expression of ERα, ERβ, PR, HER2, Ki67, PIK3CA, and MAPK using QuantiGene Assay. Thirty-one patients took letrozole 2.5mg daily and 29 did exemestane 25mg daily until the surgery (median duration 22 days). Statistical tests were two-sided. Results: Clinical characteristics were well balanced between the two treatment arms. Median % changes of Ki67 were -58%, ERα -44%, ERβ +93%, and PR -69% in LET and Ki67 -59%, ERα -30%, ERβ +135%, PR -72% in EXE. There were no significant differences of these marker changes between two agents. Dividing into 4 groups in treatment duration, 10-14 days (q1), 15-21 days (q2), 22-28 days (q3), and over 29 days (q4), LET had 2 peaks in Ki67 decreases (-69% (q1), -28% (q2), -78% (q3), -59% (q4)), whereas EXE had a peak in q2 (-62%, -77%, -49%, -26%). Ki67 increasing cases including primary resistance and tachyphylaxis were 5 (16%) in LET (3 in q2 and 2 in q4) and 3 (10%) in EXE (one of each in q2-4). All 8 cases had increases of ERβ, PIK3CA, and MAPK. Conclusions: Although both LET and EXE for short duration had significantly decreased Ki67 mRNA level irrespective of treatment duration, no significant differences was found between two agents. Tumor resistance with AIs may be associated with the other pathways.
Sirolimus Yields High Response Rates in Hematopoietic Allograft Recipients with Steroid-Refractory Acute Graft-Versus-Host Disease.
Authors: Joseph A. Pidala, Daanish Hoda, Norma Salgado-Vila, Jongphil Kim, Janelle Perkins, Ryan Bookout, Teresa Field, Lia Perez, Ernesto Ayala, J. Leonel Ochoa-Bayona, Jyotishankar Raychaudhuri, Melissa Alsina, John N Greene, William E. Janssen, Hugo F. Fernandez, Claudio Anasetti, Mohamed A Kharfan-Dabaja
Journal: Blood (2009)
An open-labeled, multicentric clinical study of cetuximab combined with intensity-modulated radiotherapy (IMRT) plus concurrent chemotherapy in locoregionally advanced (LA) nasopharyngeal carcinoma (NPC): A 2-year follow-up report.
Authors: Chun-yan Chen, Chong Zhao, Li Gao, Jin-yi Lang, Jian-ji Pan, Chao-su Hu, Feng Jin, Ren-sheng Wang, Conghua Xie, Tongyu Lin, Tai-xiang Lu
Journal: Journal of Clinical Oncology (2012)

5535 Background: To evaluate the safety and efficacy outcomes of concurrent cetuximab plus IMRT and cisplatin in Chinese patients with LA NPC. Methods: Patients with primary stage III-IVb (UICC/AJCC 2002 staging system) and non-keratinizing NPC were enrolled in this prospective, multicentric, phase II study. Cisplatin (80mg/m 2 ,q3week) and cetuximab (400mg/m 2 one w before radiation, and then 250mg/m 2 /w) were given concurrently. The prescription dose of IMRT to GTVnx (primary tumor in nasopharynx) was 66 Gy - 75.9 Gy, GTVnd (positive cervical lymph nodes) was 60 Gy - 70Gy, The response rate was evaluated according to RECIST 1.0 criteria, and adverse events (AEs) were graded according to NCI CTCAE V3.0 criteria. Results: From July 2008 to April 2009, 100 patients were enrolled (74 male), with median age of 43 years. The proportion of stage III, IVa and IVb patients were 71%, 22% and 7% respectively. 99% of enrolled patients completed the planned treatment. AEs were within the expected range and manageable. No toxic death occurred during the treatment. Acneiform skin eruptions, mucositis, in-field dermatitis, xerostomia and neucopenia were the most common seen AEs, with 64% grade 2/3 acneiform eruptions, 26% grade 2/3 in-field dermatitis, 90% ≥ grade 2 mucositis (2 cases of grade 4 mucositis with spontaneous bleeding), 40% ≥ grade 2 xerostomia and 8% grade 2/3 neucopenia. With a median follow-up time of 23.5 months, the 2 year overall survival (OS), disease-free survival (DFS), local recurrence-free survival, regional (cervical lymph node) recurrence free survival and distant metastasis-free survival rates for the ITT population were 91%, 89%, 90%, 90% and 89%, respectively Multivariate analysis showed that N stage was the only prognostic factor for OS (p=0.0392, HR=2.946) and DFS (p=0.0062, HR=4.246) in these patients. Conclusions: Cetuximab combined with IMRT plus concurrent cisplatin in patients with LA NPC shows satisfactory 2-year locoregional control rate and 2-year overall survival. The combination seems to be well tolerated with a manageable side-effect profile.
Comparison of Standard to Split-Dose TPF Induction Chemotherapy followed by Bio-radiation for LASCC of the Head and Neck: Results of the ICRAT randomized Phase II Study.
Authors: Volker Budach, Ulrich Keilholz, Jan D Raguse, Rainald Knecht, Silke Tribius, Chia-Jung Busch, Oliver Koelbl, Matthias Hautmann, Andreas Schreiber, Arne Gruen, Eva-Tessina Becker, Inge Tinhofer, Carmen Stromberger
Journal: Journal of Clinical Oncology (2015)

e17042 Background: TPF induction chemotherapy (IC) is a reasonable treatment option for locally advanced (LA) squamous cell carcinoma (SCC) of the head and neck (HN). However, substantial toxicity may compromise compliance and thereby also treatment efficacy. ICRAT is a randomized 3-arm phase 2 trial evaluating efficacy and safety of two TPF-IC regimens followed by bio-radiation (BRT) vs. concurrent PF chemoradiation (CRT) for chemo-/radiation-naive LASCCHN. Methods: Stage IV oro-/hypopharynx/oral cavity LASCC were randomly assigned to either 3 cycles of standard TPF-IC (arm A) with TP (75 mg/m2, each day 1) and F (750 mg/m2/24h days 1-4) or split-course TPF-IC (arm B) with TP (40 mg/m2, each days 1 and 8) and F (1500 mg/m2/24h days 1 and 8) vs. PF-CRT alone (arm C). Progression after first cycle of TPF-IC in arm A or B led to cross over to BRT with 72 Gy. Responders (complete: CR; partial: PR) and stable disease patients received 3 cycles of TPF-IC followed by weekly cetuximab (250 mg/m2, initial loading dose 400 mg/m2) with hyperfractionated accelerated RT of 72 Gy/6 weeks vs. concurrent PF-CRT (P: 30mg2 weekly x 6, F: 600 mg/m2/24h days 1-5). We used an exploratory study design. Composite endpoints were response (RECIST1.1), acute hematologic toxicities (CTCAE v.4.02), compliance of TPF-IC and on time application of BRT. Results: 94 patients were randomized (arm A: 34, arm B: 30, arm C: 30). Here we focus on the results of arm A and B. Best response was similar after TPF-IC for both arms (CR/PR: A: 88%, B: 83%). Hematologic toxicities were not reduced by split-course TPF-IC (neutropenia G4/5: arm A 29%/0% vs. arm B 13%/3%; thrombocytopenia G4: A 3% vs. B 0%). One patient died from sepsis in arm B after 1st cycle of TPF-IC and one in 4th week of BRT. Compliance to TPF-IC was 77% vs. 57%, on time BRT (day 70±7 after 1st TPF-IC) 85% vs. 73%, BRT completed 94% vs. 90% for arm A vs. B, respectively. Conclusions: Split-course TPF-IC did not improve safety or efficacy over standard TPF-IC and was per trend associated with inferior treatment compliance. Standard TPF-IC should not be modified outside of clinical trials. Secondary end-points and long-term follow-up are still pending. Clinical trial information: No special number.
A retrospective study from the Royal Marsden Hospital (RMH) of patients with malignant perivascular epithelioid cell tumors (PEComa) receiving treatment with sirolimus (SI) or temsirolimus (TSI).
Authors: Joanna Vitfell Pedersen, Charlotte Benson, Nina Tunariu, Scott Mitchell, Cyril Fisher, Khin Thway, James M. G. Larkin, Michelle Scurr, Ian Robert Judson
Journal: Journal of Clinical Oncology (2012)

10038 Background: Perivascular epithelioid cell tumors (PEComas) are rare tumors driven by tuberous sclerosis complex gene mutations causing upregulation of mTOR. Two studies reporting a total of five patients (pts) have described the treatment of PEComa by mTOR inhibition. We report the outcome of 7 pts with PEComa treated with SI or TSI at RMH. Methods: A retrospective analysis was performed on all pts with PEComa referred to the Sarcoma unit at RMH between 2000 and 2011. Data collected included gender, performance status, site of primary tumour, tumour size, surgery, SI/TSI and SI/TSI dose, toxicity according to common toxicity criteria (CTC) version 2.0 and response by RECIST. Results: Five (71%) pts were female, median age was 46 years. Two (29%) had metastatic disease at baseline. Most common primary site was the gastrointestinal tract (29%). Six pts received SI, one TSI. Median treatment duration was 131 days (7-1135). TSI was given at 25 mg IV weekly. Median starting dose of SI was 3 mg daily (1-4), median highest dose was 4 mg daily (1-5). Best responses by computed tomography (CT) scan by RECIST criteria were partial response: 3 (43%), stable disease: 2 (29%) and progressive disease (PD): 1 (14%). One pt only received 7 days of SI and was therefore not evaluable. Two pts continue on treatment, 3 stopped due to PD, one stopped due to grade (gr) 3 thrombocytopenia and one due to gr 3 cough, but two weeks later had confirmed PD on CT. Other toxicities reported were generally mild (gr 1/2) and included mucositis (n:3), rash (n:2), fatigue (n:1), anaemia (n:1), tooth pain (n:1) and oedema (n:1). One pt experienced a grade 3 trigeminal nerve pain leading to dose reduction in SI. Therapeutic drug monitoring was not performed. Conclusions: Our study confirms that SI and TSI are well tolerated with good clinical response and supports the continuous administration of SI or TSI for PEComas. A median treatment time of only 131 days indicates that most pts have a good response to treatment, but responses are sometimes short-lived and further treatment options are needed, justifying further research into inhibitors of this signalling pathway.
David Oliver: Getting real about care closer to home
Authors: David Oliver
Journal: BMJ (2017)

There’s a growing consensus about how we must change to ensure sustainable future health services. Its essence is: let’s focus more on public health, prevention, and wellbeing; enhance primary and wider community support for people with long term conditions; and, during acute crises, help patients spend less time in hospitals—or none at all—repurposing resources and staff away from hospital buildings.

In England we see such ambitions and rhetoric in political pronouncements and in key documents such as the NHS Five Year Forward View ,1 sustainability and transformation plans (STPs),2 and position papers from …