tbuckley/cabot-search huggingface dataset:
A phase II study of S-1 and concurrent thoracic radiotherapy (TRT) for elderly pts with locally advanced non-small cell lung cancer (LA-NSCLC): Okayama Lung Cancer Study Group trial 0801.
Authors: Yoshiro Fujiwara, Katsuyuki Hotta, Keisuke Aoe, Naoyuki Nogami, Masahiro Tabata, Shingo Harita, Shinobu Hosokawa, Kenichi Gemba, Nagio Takigawa, Mitsune Tanimoto, Katsuyuki Kiura
Journal: Journal of Clinical Oncology (2014)

7576 Background: Although thoracic irradiation is one of the standard therapies in elderly pts with LA-NSCLC, its treatment outcome is still poor. We previously reported safety profiles of S-1, an oral fluoropyrimidine possessing a radio-sensitizing effect, and concurrent TRT in such population [Lung Cancer 2011]. The objective of this study was to assess the efficacy and safety of S-1 with concurrent TRT for elderly pts with LA-NSCLC. Methods: Pts with stage III, aged ≥76 years and PS 0-1, and without any prior chemotherapy were eligible for this study. ps were treated with S-1 (40 mg/m²/dose b.i.d. on days 1-14 and 29-42) and TRT (60 Gy/30 fr over 6 weeks starting on day 1). Primary endpoint was response rate (RR), and required sample size was 30 pts, with a rate of 50% would be the lower limit of interest, with α = 0.05 and ß = 0.20. Results: Between 2007 and 2012, 30 pts were enrolled (24 men; median age, 79 years; PS 0, 15; IIIA, 20; Sq, 12). Median Charlson score was 1 ranging from 0 to 3. The proportion of actual dose schedule relative to the planned one of S-1 and TRT was 95 and 98%, respectively. Partial response was observed in 19 pts (63%; 95% confidence interval: 45-82%), which did not meet the endpoint. At the time of this analysis, 26 pts recurred at the local and distant sites in 18 and 10 pts, respectively. At a median follow-up of 23.7 months, median progression-free survival and MST were 13.0 months and 65.2 months, respectively. No difference in efficacy (response and survivals) was observed stratified by histology (sq vs. non-sq). Toxicities were generally mild, including G3/4 neutropenia (13%), G3 febrile neutropenia (7%) and G3 pneumonitis (10%). No one developed Gr3/4 esophagitis. No toxic deaths occurred. Conclusions: Although this study did not meet the primary endpoint, concurrent S-1 and radiotherapy yielded a favorable survival data. Also, it was well-tolerated in elderly pts with LA-NSCLC. Clinical trial information: UMIN000013077.
Phase II study of XL184 (cabozantinib) in recurrent or metastatic endometrial cancer: A trial of the PMH, Chicago, and California Phase II Consortia.
Authors: Michelle Wilson, Neesha C. Dhani, Hal W. Hirte, Stephen Welch, Helen Steed, Lainie P. Martin, Stephanie Lheureux, Cristina Martin-Lorente, Helen Mackay, Marcus O. Butler, Lisa Wang, Judy Quintos, Katie Allen, Lynda Roman, John Joseph Wright, Amit M. Oza
Journal: Journal of Clinical Oncology (2014)

TPS5629 Background: Recurrent endometrial cancer (EC) has a poor prognosis with few therapeutic options. Targeting angiogenesis through VEGF inhibition has demonstrated real but limited efficacy. Simultaneous inhibition of angiogenesis and putative resistance mechanisms may provide more durable therapeutic responses. MET/HGF (hepatocyte growth factor) paracrine signaling has been implicated in more aggressive tumour biology, angiogenesis and resistance to VEGF targeting in EC. XL-184 (cabozantinib) is an orally bioavailable, multi-targeted inhibitor with activity against MET and VEGFR2 in addition to TIE2, RET, AXL and KIT. Methods: This phase II, multicenter single arm trial has a planned enrollment of 36 pts utilizing a Simon 2-stage design to evaluate co-primary endpoints of response rate and 12 week progression-free-survival (PFS) in pts with serous, endometrioid or mixed histology EC (experimental cohort). Eligible pts must have radiographic progression after 1 line of chemotherapy for metastatic disease, or progression within 12 months of adjuvant chemotherapy; prior radio- and hormonal therapy is allowed. Stage I has a planned accrual of 18 pts, study will proceed to stage II with observation of > 2 partial responses (PR) and > 6 12-wk PFS. Pts are also accrued to an exploratory cohort (maximum 30 pts) of rare histology EC (clear cell, carcinosarcoma). XL-184 is administered at a starting dose of 60mg orally once daily on a continuous 28 day cycle. Adverse event (AE) reporting is as per CTCAE v4.0. Pts undergo first CT evaluation after 1 cycle, those with SD or PD and ≤ grade 1 toxicity are eligible for dose escalation. Response assessment is completed every 2 cycles (starting with cycle 3) and per RECIST 1.1. Correlative studies will explore associations between tumour response and baseline mutational and met amplification status. To date 14 (experimental) and 6 (exploratory) pts have been enrolled. Median age is 64 (range 51-80). All pts have received chemotherapy and 70% prior radiation. 44 cycles have been completed (median 2 range 1-5). Once the final pts have been accrued to the experimental arm, a decision to proceed to stage II will be made. Clinical trial information: NCT01935934.
BRCA1- versus non-BRCA1/2-associated breast cancer (BC): Tumor characteristics and impact of prognostic and treatment factors
Authors: C. Seynaeve, M. Tilanus-Linthorst, H. Meijers-Heijboer, C. Alvez, J. Blom, C. Crepin, A. Van Den Ouweland, M. Menke-Pluijmers, J. Klijn, C. Brekelmans
Journal: Journal of Clinical Oncology (2004)

9557 Background: Genetic testing made it possible to identify persons at high-risk for BC. Most hereditary BC, however, cannot be attributed to mutations in BRCA1/2. The characteristics and the impact of prognostic and treatment factors in non-BRCA1/2- as compared to BRCA1-associated BC are insufficiently known. Methods: From the database of our family cancer clinic, we selected consecutive BC pts. from families with a BRCA1 mutation (n=230) and without an identified BRCA1/2 mutation (non-BRCA1/2) (n=236), diagnosed between 1980 and 2001. Tumorcharacteristics, treatment and follow-up data were extracted from hospital records. Cox proportional hazards modelling was used to investigate the impact of classical prognostic (age, tumorstage, period of diagnosis) and treatment factors (chemotherapy, prophylactic bilateral salpingo-ovariectomy (PBSO) on distant disease free (DDFS) and overall survival (OS). Results: Mean age at BC diagnosis was 41yr (24–82) for BRCA1 and 45yr (23–77) for non-BRCA1/2 pts., median follow-up 4.9 and 6.1yrs. Tumorcharacteristics in BRCA1 carriers versus non-BRCA1/2 cases were: T1 in 51/63%; node negative disease in 65/52%; positive estrogen (ER) and progesterone receptor (PR) status in 26/75% and 28/83% respectively. Chemotherapy was given in 44/37%, PBSO performed in 39/7% respectively. Five, 10- and 15-yrs DDFS rates were 72%, 62% and 53% for BRCA1, and 75%, 62%, and 56% for non-BRCA1/2 patients, respectively. For OS this was 76%, 64% and 61% in BRCA1 versus 86%, 71%, and 61% for non-BRCA1/2 cases. In the multivariate analysis, independent prognostic factors for DDFS and OS were tumor stage (TN) (p<0.03), adjuvant chemotherapy (p < 0.01) and PBSO (p<0.001) in BRCA1 carriers, while in non-BRCA1/2-associated BC only TN tumor stage (p<0.02) was significantly determinative. Conclusion: our data indicate that BRCA1 and non-BRCA1/2-associated BC are different entities. Tumorstage is an independent prognostic factor in both BRCA1- and non-BRCA1/2- associated BC. Further, in BRCA1-BC, adjuvant chemotherapy and PBSO have significant impact on survival. No significant financial relationships to disclose.
Small cell lung cancer (SCLC) among patients who are never smokers.
Authors: Anna M. Varghese, Helena Alexandra Yu, Helen H. Won, Camelia S. Sima, Gregory J. Riely, Lee M. Krug, Natasha Rekhtman, Mark G. Kris, Michael F. Berger, Maureen Frances Zakowski, Maria Catherine Pietanza
Journal: Journal of Clinical Oncology (2013)

7593 Background: Although most patients (pts) with SCLC are current or former smokers, SCLC has been reported in pts who are never smokers, most recently in pts with EGFR-mutant lung cancers who develop acquired resistance (AR) to EGFR tyrosine kinase inhibitors (TKIs). We describe clinical, pathologic, and molecular characteristics of never-smoking pts with SCLC at diagnosis and in the AR setting. Methods: We identified cases through systematic review of pts seen at MSKCC from 2005 – 2012. Smoking history was obtained prospectively. SCLC diagnosis was confirmed by expert pathology review. We collected age, sex, stage, treatment, and survival data. EGFR, KRAS, PIK3CA, and ALK testing and next generation sequencing of 279 cancer genes was performed on available samples. Results: 2.2% (23/1040, 95% CI 1.5 to 3.3%) of pts with SCLC seen at MSKCC were never smokers: 61% women, median 64 years, 74% extensive stage, and 22% with brain metastases at diagnosis. 83% (19/23) had de novo SCLC, whereas only 17% had SCLC as AR to EGFR TKI after treatment for EGFR-mutant lung cancers, all of whom had persistent EGFR mutation confirmed at resistance. Median survival from SCLC diagnosis is 23 months (95%CI: 11-26) for all pts and 23 months (95% CI: 8–27) for the 19 pts with de novo SCLC. Pathologic review demonstrated 19 cases of pure SCLC and 4 mixed histology cases with SCLC and other histologies. Treatment history was available for 15/19 pts with de novo SCLC: 53% etoposide-platinum sensitive. ALK rearrangement and KRAS mutations were identified in 0/5 and 0/10, respectively. One pt with de novo mixed SCLC and adenocarcinoma had an EGFR mutation and another pt with de novo pure SCLC had EGFR and PIK3CA mutations. Mutations were identified in p53 and Rb1 with amplification in TERT in 1 sample to date tested with next generation sequencing. Conclusions: 2% of pts with SCLC are never smokers. While transformation to SCLC can occur in the setting of AR to EGFR TKI, de novo SCLC occurs in the majority of our never smokers with this disease. EGFR mutations uniformly exist in SCLC in the AR setting. EGFR mutations were rare, and we found no KRAS mutations or ALK rearrangements. Comprehensive, multiplexed genotyping can aid in providing optimal care and facilitate research in this unique population.
CT and PET-CT for detection of synchronous lesion in patients with colorectal cancer obstruction.
Authors: Hyun Ho Choi, Sang Woo Kim, Hyung-Keun Kim, Sung Soo Kim, Hiun-Suk Chae
Journal: Journal of Clinical Oncology (2017)

581 Background: Full preoperative colonic evaluation is recommended to exclude synchronous lesions. In patients with occlusive colorectal cancers, preoperative colonoscopy may not be possible because of narrowing of the lumen. After colonic stent placement, colonoscopy to the proximal part of the obstruction is feasible. However, a complete preoperative colonoscopy was not possible in some cases. The aim of our study was to evaluate the efficacy of preoperative CT and PET-CT for detection of synchronous neoplasms compared with colonoscopy in colorectal cancer obstruction patients who underwent colonic stent. Methods: A retrospective chart review of 205 patients who performed endoscopic colon stent placement for acute malignant colorectal obstruction between January 2010 and October 2015. To find synchronous cancer and other precancerous lesion, we reviewed CT, PET-CT finding and colonoscopic image. The results of CT and PET-CT were compared with the finding of the colonoscopy, which was remains the most reliable method for the detection of synchronous neoplasm. Results: Of the 205 patients with colonic stent placement, 115 patients underwent CT, PET-CT and preoperative colonoscopy passing through the colonic stent. On preoperative colonoscopy, 3 of 115 patients (2.7%) had synchronous cancers and 11 of 115 patients (9.6%) had large polyps (tubulovillous adenoma with high grade dysplasia). On CT and PET-CT, all synchronous lesions were detected. But among the eleven polyps, nine polyps had not been seen at CT and PET-CT. Conclusions: Our study indicates that CT and PET-CT were feasible and useful method of evaluating the entire colon to exclude synchronous colonic lesions in patients with acute colon obstruction after an effective stent placement. But colonoscopy should be performed shortly to find out precancerous lesion especially adenoma with high grade dysplasia.
The City of Hope (COH) performance excellence program (PEP): A physician incentive program to improve health care performance (HCP) in an academic medical center.
Authors: Joseph C. Alvarnas, Tricia Kassab, Priscilla Avanessian, Michael Pierce, Alexandra M. Levine
Journal: Journal of Clinical Oncology (2013)

e17556 Background: The Affordable Care Act (ACA) introduced a pay for performance model focused on: safety, timeliness, effectiveness, efficiency, patient-centered, equitable care. COH is an NCI sponsored Comprehensive Cancer Center, focused on cancer care. Methods: In 2011, a physician led team with representation from finance, QRRM, nursing and legal identified 13 quality measures (QM) where opportunities for improvement (OFI) existed. Selection criteria included measurability, importance, applicability to ACA, physician impact, return on investment and national importance. The QM include HCAHPS score, Healthcare Associated Infection rate (HAI), quantity of blood products internally produced (BP), coder response rate (RR), use of sepsis bundle orders, time to new patient appointments (NPA), OR 1st case on-time starts, timeliness of adjuvant therapy for breast/colon cancer patients, SCIP composite score and use of VTE prophylaxis orders. HCP for the first 4 QM was assessed based upon institutional performance; 6 QM were assessed upon departmental performance. There were 3 build measures (BM): creating a system to obtain advanced directives (AD) on all new patients, creating a system for effective communication with referring physicians and 4 departmental BM based on best practices. Results: PEP performance was assessed between 5/1/12-12/31/12. 174 physicians in 11 departments were eligible for a $2.05 million incentive pool. QM were evaluated using a tiered bonus structure. Significant improvements were seen in HAI, BP production, SCIP, OR starts and timely adjuvant therapy. There were improvements in the use of VTE orders, but aggregate performance fell below payment threshold. The build measure for AD was completed. Conclusions: (1) PEP is an effective tool for physician engagement in an academic medical center. (2) PEP enhanced alignment between the medical group, hospital, nursing and administration. (3) PEP was effective in improving HCP in less than one year from its inception. [Table: see text]
Prevalence of oligoprogressive, metastatic castration-resistant prostate cancer (mCRPC) amenable to stereotactic ablative radiotherapy (SABR) in men undergoing abiraterone acetate (AA) therapy.
Authors: Erica McDonald, Sierra Cheng, Vanessa S. Arciero, Ronak Saluja, Katherine A. Zukotynski, Patrick Cheung, Urban Emmenegger
Journal: Journal of Clinical Oncology (2017)

e587 Background: SABR is increasingly used for the treatment of men with oligometastatic prostate cancer, including patients (pts) presenting with oligoprogression. The latter is a clinical situation where a limited number of metastatic tumor sites progress (usually defined as ≤ 3-5), while all other metastases are controlled by a given systemic therapy. The frequency of oligoprogression potentially amenable to SABR is unknown. Methods: Thus, in a retrospective chart analysis we studied the progression pattern of 35 men with chemotherapy-naïve mCRPC undergoing AA therapy, and of 20 men undergoing AA therapy after docetaxel chemotherapy. Applying RECIST1.1 and/or PCWG2 criteria, pts were considered SABR candidates if they radiologically progressed in ≤ 5 distinct metastatic locations, while all other metastases were stable or responding. Results: In chemotherapy-naïve men, pre-AA metastatic lesions were located in bone (94%), lymph nodes (49%), lungs (17%) and liver (3%), whereas progression during AA therapy occurred in bone (89%), lymph nodes (49%), lungs (14%) and liver (9%). 12 pts (34%) fulfilled the criteria of oligoprogression with a median of 2 progressive lesions/pt (range 1-5). 8 pts presented with bone progression only, 3 with nodal progression, and 1 pt with combined bone/nodal progression. Post-docetaxel pts had pre-AA metastatic lesions located in bone (75%), lymph nodes (35%), lungs (5%) and liver (5%). Progression during AA therapy occurred in bone (80%), lymph nodes (75%), lungs (20%) and liver (5%). Only 1 pt met oligoprogression criteria with a single progressive bone metastasis. Conclusions: A sizeable number of men with chemotherapy-naïve mCRPC progressing during AA therapy might be considered for SABR. By contrast, progression of post-docetaxel mCRPC treated with AA is typically widespread. Further efforts are needed to identify criteria for oligoprogressive pts most suitable for SABR with sustained benefit versus men that may progress rapidly with widespread metastases following radiotherapy.
Phase I-II study of the histone deacetytase inhibitor vorinostat plus sequential weekly paclitaxel and doxorubicin-cyclophosphamide in locally advanced breast cancer.
Authors: Yifan Tu, Dawn L. Hershman, Christine M. Pellegrino, Eleni Andreopoulou, Della Makower, Susan Fineberg, Kapil N. Bhalla, Kevin Kalinsky, Karen Fehn, Min Huang, R. Katherine Alpaugh, Joseph A. Sparano
Journal: Journal of Clinical Oncology (2014)

598 Background: HDACs regulate chromatin remodeling and gene transcription. Vorinostat (V) is a panHDAC inhibitor that sensitizes breast cancer (BC) cells to taxanes and trastuzumab. Methods: 55 patients (pts) with clinical stage IIA-IIIC BC received 12 weekly doses of paclitaxel (P)(80 mg/m2) plus V on days 1-3 (200 mg BID [N=4], 300 mg BID [N=51]) of each P dose plus trastuzumab (if HER2-positive), followed by doxorubicin/cyclophosphamide (AC-60/600 mg/m2 every 2 weeks and pegfilgrastim), The trial was powered to detect an improvement in pathologic complete response (pCR) rate from 30% to 55% (α=0.10, β=0.10) in stratum A (HER2+) and stratum B (triple negative), and from 15% to 40% in stratum C (ER+, HER2-). Immunohistochemistry was done on pretreatment core biopsies for HDAC6, p27, p21, Hsp70, and Ki67, and 3 pts had biopsies done before and after the third V dose for Western blot analysis. Results: There were no dose limiting toxicities at either V dose level. Breast/nodal pCR occurred in 13/24 evaluable pts in stratum A (54%, 95% confidence intervals [CI] 34%, 74%), 4/15 evaluable pts in stratum B (27%, 95% CI 95% CI 11%, 52%), and none of 12 evaluable patients in stratum C. Residual cancer burden (RCB) scores were 0-1 in 19 (79%, 95% CI 59%, 91%), 7 (47%, 95% CI 21%, 71%), and 1 (8%, 95% CI 0.4%, 35%) pts in stratums A, B, and C, respectively. Mean/median HDAC6 expression did not differ in each stratum or correlate with pCR. Mean P21 expression was higher in stratum A than B (p=0.03), and HSP70 expression was higher in stratum C than A (p=0.02). By Western blot, V suppressed HDAC6, increased acetylation of HSP90 and alpha-tubulin, and reduced levels of HSP90 client proteins (eg. HER2/neu, pAKT) in vivo. Conclusions: Combination of V with weekly paclitaxel and trastuzumab followed by AC induces higher than expected pCR rate in locally advanced HER2/neu-positive breast cancer. V induced biological effects in vivo that may enhance the antitumor effects of paclitaxel and trastuzumab and contribute to the efficacy of this combination. Clinical trial information: NCT00574587.
Rictor amplification to define a novel and unique subset of lung cancer patients.
Authors: Haiying Cheng, Jeffrey S. Ross, Kai Wang, Abraham Chachoua, Xuewen Liu, Balazs Halmos, Vincent A. Miller, Philip J. Stephens, Roman Yelensky, Doron Lipson, Siraj M. Ali, Geoff Otto, Matthew J. Hawryluk, Roman Perez-Soler, Bilal Piperdi
Journal: Journal of Clinical Oncology (2014)

8027 Background: Recent advances in molecularly tailored therapy have shifted the treatment paradigm in lung cancer. We recently identified amplification of RICTOR, a key component of the mTORC2 complex, as a new and sole genomic alteration in an 18-year-old never smoker with lung adenocarcinoma. We hypothesizethat RICTOR amplification, unlike previously reported molecular changes in the PI3K/AKT/mTOR pathways, may identify a new subgroup of lung cancer patients amenable to molecularly targeted therapy. Methods: The index patient had RICTOR amplification identified by next generation sequencing (NGS)- genomic profiling of 182 cancer-related genes performed with extracted DNA from FFPE specimens. We then reviewed the database of 1128 lung cancer patients who had profiling performed by Foundation Medicine. Additionally, we examined the in vitro cytotoxicity of 6 classes of drugs against different components of the PI3K/AKT/mTOR pathways in RICTOR-amplified H23 lung cancer cells. Results: RICTOR amplification in the index case was confirmed by FISH and IHC of RICTOR and its downstream targets. RICTOR amplification was found in 8.2% (92/1128) lung cancer patients from the NGS database. In 11% (10/92) of cases, RICTOR amplification was the only potentially actionable target. Additionally, 13% (12/92) and 27% (25/92) of these patients had concomitant alterations in KRAS and EGFR, exclusively in lung adenocarcinomas. One third of the patients (29/92) had alterations in other genes within the PI3K/AKT/mTOR pathway. Among all the examined agents targeting the PI3K/AKT/mTOR pathways, BEZ235 (dual PI3K/mTOR inhibitor) and AZD2014 (dual mTOR1/2 inhibitor) were the most active in RICTOR-amplified H23 lung cancer cells. As a proof of concept, our index patient has been treated on a phase I clinical trial with a dual mTOR1/2 inhibitor (CC223) and has had stable disease for over 8 months. Conclusions: RICTOR amplification may define a novel and unique molecular subset of lung cancer patients. Our observation provides the rationale for testing RICTOR amplification as a potential biomarker for targeted therapy with mTOR1/2 inhibitors in lung cancer patients.