tbuckley/cabot-search huggingface dataset:
Non breast cancer outcomes in women who attend breast screening.
Authors: Euan Thomas Walpole, Nathan Dunn, Hazel Harden, Colin Furnival, Kathleen Taylor, Elizabeth Evans, Julie Moore, Tracey Guan, Shoni Philpot, Jeannette Young
Journal: Journal of Clinical Oncology (2018)

e13579 Background: In Queensland, Australia, all women aged 50-74 are offered free breast screening. The plan evaluates non breast cancer outcomes for screened and non screened populations aged 50-65 years with 10 year follow up. Methods: Using data linkage, state cancer registry, hospital admission, treatment and death registry were combined with mammographic screening datasets. Women with prior cancer diagnosis ( < 2000) were excluded. Follow up continued till 12/ 2015. Results: Between 2000-2005, 269,935 were invited. 211,757 (78.4%) had ≥1 mammogram. There was no difference between the groups re age, socioeconomic status(SES) or rurality. In the screened group: the incidence of lung(HR 0.73, p < 0.001), cervix(HR 0.41, p < 0.001), head & neck(HR 0.74, p = 0.001), oesophageal(HR 0.7, p = 0.01) cancers was less while colorectal increased 14.3%(p < 0.001). Major surgical resection was more likely in lung(RR1.75, p < 0.001), cervix(RR2.0, p < 0.001), oesophageal(RR2.49, p = 0.01), ovarian(RR1.29, p < 0.001), colorectal(RR1.02, p = 0.02). Radiotherapy use was less in cervix(RR 0.8, p = 0.002). More IV chemotherapy in lung (RR1.18, p < 0.001), colorectal(RR1.09, p = 0.03) and pancreas (RR1.19, p = 0.049) but less in cervix(RR0.73, p = 0.001). Localised cancers was more common(RR 1.24, p < 0.001) - lung(RR1.17, p = 0.009), cervix(RR1.31, p = 0.014), head & neck(RR1.29, p = 0.004), ovary(RR1.37, p = 0.025), colorectal(RR1.23, p < 0.001), pancreas(RR1.37, p = 0.025). No record of major surgery, radiation or IV systemic therapy was 1.9 times higher in the unscreened group. Non breast, cancer mortality is 35% lower in the screened group(p < 0.001) - 37.5% lung, 30.6% ovarian, 31.5% colorectal, 78.8% cervical, 60.5% head & neck, 45.6% oesophageal(all p < 0.001). Non cancer mortality was reduced by 41% (p < 0.001) and 45% in cardiovascular (p < 0.001). Multivariate analysis adjusting for age, SES, rurality and stage confirmed these effects. Conclusions: This data supports that woman who attend breast screening have health behaviours that reduce other cancer and non cancer disease mortality. The main cancer effects were reduced incidence and lower stage of presentation with more use of major surgery. Further data will be able for presentation. Supported by AusHi
A gene expression prognostic signature for overall survival in patients with high-grade serous ovarian cancer.
Authors: Joshua Millstein, Timothy Budden, Michael Anglesio, Aline Talhouk, Alicia Beeghly-Fadiel, Andrew Berchuck, Georgia Chenevix-Trench, Anna deFazio, Peter A. Fasching, Simon Gayther, María García, Ellen L. Goode, Michelle Henderson, Gottfried E. Konecny, Sandra Orsulic, David Huntsman, David Bowtell, Jennifer Doherty, Paul Pharoah, Susan J Ramus
Journal: Journal of Clinical Oncology (2018)

5583 Background: Median survival for high-grade serous ovarian cancer (HGSOC) patients is 3-4 years with a wide range of outcomes. Gene expression patterns have been reported to be predictive of outcome, but results have been inconsistent. The aim of this study was to assess the predictive utility of genes previously associated with outcome and to develop a clinically useful predictor for overall survival (OS). Methods: We identified 200 genes associated with prognosis from a meta-analysis of previously published gene expression profiling studies in HGSOC and selected an additional 313 candidate genes. Expression in formalin fixed paraffin embedded (FFPE) HGSOC tumor tissue was measured with Nanostring for 3770 women with known OS. Regression-based and machine learning methods were used to develop a prognostic signature for OS. These approaches included stepwise regression, elastic net penalized regression, random survival forests, and component-wise gradient boosting. Models were trained and tested on approximately 2/3 of the data and the best performing model was evaluated on the remaining 1/3. Results: In single gene Cox models for OS adjusted for age and stage, there were 275 significant associations (false discovery rate (FDR) < 0.05). The two most significant genes were TAP1 (p = 2.2e-17; hazard ratio (HR) = 0.84 (0.81, 0.87)) and ZFHX4 (p = 1.3e-15; HR = 1.19 (1.14, 1.25)). Elastic net yielded the best performing signature in the training data, and in the validation data it was substantially more prognostic than any individual gene (HR = 2.42 (2.09, 2.81), scaled to 1SD). The area-under-the-curve (AUC) for the signature combined with age and stage for 5yr OS was 0.74, substantially larger than the AUC for age and stage alone (0.62). Conclusions: These data confirm previously reported or hypothesized associations between gene expression in HGSOC tumor tissue and overall survival. Our signature could be useful in designing clinical trials for patients who are destined to have poor survival, thereby delivering new agents to the patients who are in the most urgent need. Identification of genes associated with the outcome also provides the opportunity to develop targeted therapeutic approaches.
Overall survival (OS) by clinical risk category for high dose interleukin-2 (HD IL-2) treated metastatic renal cell cancer (RCC): Data from PROCLAIM.
Authors: Mayer N. Fishman, Joseph I Clark, Ajjai Shivaram Alva, Brendan D. Curti, Neeraj Agarwal, Ralph J. Hauke, Kathleen Margaret Mahoney, Helen Moon, Jonathan Treisman, Scott Tykodi, Gregory A. Daniels, Michael Morse, Michael K.K. Wong, Howard Kaufman, Nancy C. Gregory, Janice P. Dutcher
Journal: Journal of Clinical Oncology (2018)

4578 Background: Clinical risk factors continue to separate mRCC patient survival outcomes regardless of therapy. Methods: International Metastatic RCC Database Consortium (IMDC) risk criteria were utilized to assess survival among 939 mRCC patients in the PROCLAIM data base, with dates of treatment from 2006 to present. 810 patients (pts) had data for all 6 IMDC criteria and are described here. Median follow-up is 23.4 months (range 0.2 – 124 mo). Patients are grouped by prior or no prior therapy, IL-2 alone, or subsequent therapy. Some patients are in two groups. Results: The majority of patients were treatment-naïve and intermediate risk. Of the 249 patients with favorable risk, the median OS is 63.3 mo and the 2-year OS is 77.6%. Of 480 patients with intermediate risk, median OS is 42.4 mo, 2-year OS 68.2%, and of 81 patients with poor risk, median OS 14 mo, 2-year OS 40.4%. Conclusions: Among mRCC pts treated with HD IL-2, all risk groups have median and 2-year survival consistent with or better than recent reports of checkpoint or targeted therapies for RCC. Favorable and intermediate risk (by IMDC) patients treated with HD IL-2 have better OS compared with that of poor risk patients, with highest OS in favorable risk patients. Favorable risk patients treated with HD IL-2 alone have a 2-yr OS of 74%. These data continue to support a recommendation for HD IL-2 for patients with mRCC. Patient Group (numbers) Favorable Intermediate Poor All patients (810) 249 480 81 Therapy prior to IL-2 (89) 17 57 15 No prior therapy (365) 113 220 32 Therapy post IL-2 (414) 122 254 38 IL-2 alone (356) 119 203 34 2-year Overall Survival All patients (810) 77.6% 68.2% 40.4% No Prior Therapy (365) 83.6% 71.6% 53.3% Post-IL-2 Therapy (414) 81% 72.0% 46.8% IL-2 Alone (356) 73.8% 63.7% 39.8%
High-dose chemotherapy (HDCT) plus peripheral-blood stem-cell transplant (PBSCT) for patients (pts) with relapsed germ-cell tumors (GCT) and active brain metastases (mets).
Authors: Maitri Kalra, Nabil Adra, John Mckay, Rafat Abonour, Nasser H. Hanna, Lawrence H. Einhorn
Journal: Journal of Clinical Oncology (2017)

4558 Background: The optimal management of progressive brain mets in pts with GCT remains unsettled. Treatment options include chemotherapy, stereotactic or whole brain radiation (XRT), surgery, or a combination thereof. Global germ cell cancer group analysis suggested multimodality therapy improves survival probabilities in pts with brain mets at relapse (JCO.2016;1;34(4):345-51). We report our experience on managing 25 consecutive pts with relapsed GCT and progressive brain mets undergoing HDCT with PBSCT at Indiana University from 2006-2016. Methods: All pts received HDCT consisting of carboplatin 700 mg/m2 days 1-3 and etoposide 750 mg/m2 i.v. days 1-3 followed by PBSCT on day 5 for upto 2 cycles. Pts were treated with craniotomy, XRT, chemotherapy alone, or a combination of modalities. Patient and disease characteristics, management of brain mets, and outcomes were measured. Platelet transfusions were given to maintain platelet counts &gt; 30,000 and goal of &gt; 50,000 in those with signs of hemorrhage. Results: Patient characteristics and outcomes are summarized in Table 1. Median age was 27.7 years (range, 16-48). All pts had progressive brain mets at time of starting HDCT. AFP ranged 1.6 to 1130, hCG 0.5 to 25601. At median follow-up of 24.8 months (range 2.5 to 118.5 months), 11 pts (44%) were alive with NED, 2 pts were alive with relapsed disease, and 12 pts died of disease progression. 17/18 patients developed progressive CNS mets despite radiation and/or craniotomy and of those, 8 are alive with NED. Toxicity was as previously published with this regimen (N Engl J Med 2007;357:340-8). Conclusions: Patients with relapsed GCT with progressing brain mets, including those with prior locoregional therapy, are curable with HDCT. [Table: see text]
Validating a PET/CT volumetric prognostic index for non-small cell lung cancer.
Authors: Yonglin Pu, Kristen Wroblewski, Haiyan Liu, Cassie A Simon, Yulei Jiang, Mark K. Ferguson, Bill C Penney
Journal: Journal of Clinical Oncology (2016)

8516 Background: We previously developed a PET/CT volumetric prognostic staging system (PVP index) using Cox regression models to predict the hazard of death using both whole-body metabolic tumor volume (MTVWB ) and TNM staging, which has greater prognostic power than TNM stage or MTVWB alone in non-small cell lung cancer (NSCLC). This study is to validate its prognostic accuracy in a different NSCLC population. Methods: We performed an IRB-approved retrospective review of 667 patients with a new NSCLC diagnosis and with FDG PET/CT scans obtained with a number of different scanners (302 patients with a Siemens Reveal HD scanner, 133 with a Siemens mCT scanner and 232 with outside hospital scanners) from 2004 to 2015. Clinical TNM stage, initial PET MTVWB , and long-term survival data were collected. The PVP index was calculated for each patient based on their MTVWB and TNM stage using our published formula: 0.360*ln(MTVWB ) + 0.424*I(TNM = III) + 0.890*I(TNM = IV), with the indicator function I(·) yielding a value of 1 when its argument is true and 0 otherwise. Kaplan-Meier survival analysis, the log-rank test and univariate Cox regression analysis with Gonen and Heller's Concordance Index (GHCI) were used. Results: Their median age was 68 years, with 55% women and median follow-up among 289 survivors of 39 months. Clinical TNM stages were I (30%), II (11%), III (30%), and IV (29%). Tumor histology was adenocarcinoma (54%), squamous carcinoma (28%) and other types (18%). 38% of patients had surgery, 59% had chemotherapy, and 40% had radiation. PVP was inversely associated with overall survival (OS) (p < 0.001). Five year OS rates of patients in the 1st, 2nd, 3rd and 4th PVP index groups were 58%, 30%,18%, and 12%, respectively. Univariate Cox regression analysis showed significant association of the PVP index with OS (HR = 2.07, 95% CI = 1.84-2.32, p < 0.001). The PVP index yielded greater discriminatory power (GHCI = 0.68) than those of TNM stage (GHCI = 0.66, p < 0.001). Conclusions: This study used a large validation cohort of NSCLC patients, imaged on a number of PET/CT systems, to confirm that the PVP index has good discriminatory ability and greater prognostic value than TNM stage alone.
Periprocedural management of patients undergoing liver resection or liver-directed therapy for neuroendocrine tumor metastases.
Authors: Daniel Kwon, Claire Mulvey, Alan T Paciorek, Hilary Chan, Lingzhong Meng, Li Zhang, Eric K. Nakakura, Nicholas Fidelman, Emily K. Bergsland, Katherine Van Loon
Journal: Journal of Clinical Oncology (2017)

e15689 Background: Carcinoid crisis is a life-threatening event caused by release of vasoactive substances from neuroendocrine tumors (NETs). Octreotide is often used in the periprocedural setting as prophylaxis against carcinoid crisis; however, there is no standardized protocol for its use. We aimed to describe the periprocedural management of patients with metastatic NETs who underwent liver-directed procedures at UCSF. Methods: We identified 54 patients with NETs with hepatic metastases who underwent either liver resection/ablation (n = 30) or liver-directed embolization (n = 24) between 2012 and 2016. Anesthesia records and clinical data were abstracted. Carcinoid crisis was defined by physician documentation. Hemodynamic instability was defined as ≥10 minutes of systolic blood pressure &lt; 80 mmHg or &gt; 180 mmHg or heart rate &gt; 120. Pearson chi-squared tests were used to test associations with three outcomes: crisis, instability, or none. Results: Three (6%) patients were documented to have developed carcinoid crisis. Another 14 (26%) patients developed hemodynamic instability. Of 16 patients who received preprocedural octreotide, 1 (6%) had a carcinoid crisis and 5 (31%) developed hemodynamic instability. History of carcinoid syndrome, degree of hepatic involvement, and use of pre or intraprocedural octreotide were not associated with carcinoid crisis or at least hemodynamic instability. Patients undergoing embolization were less likely to develop hemodynamic instability versus those undergoing liver resection (17% vs 43%, Pearson chi-squared p = 0.04). Conclusions: Occurrence of documented carcinoid crisis was low in this high-risk population. However, a significant proportion of patients developed hemodynamic instability, suggesting that carcinoid crisis is a spectrum diagnosis and may be clinically under-recognized. Use of octreotide was not associated with risk of carcinoid crisis or hemodynamic instability; however, this analysis was limited by our modest sample size at a single institution. There remains a need to establish an objective definition of carcinoid crisis and to inform standardization of periprocedural use of octreotide for at-risk patients.
Clinical next-generation sequencing in sarcomas.
Authors: Roman Groisberg, David S. Hong, Filip Janku, Sarina Anne Piha-Paul, Vinod Ravi, Robert S. Benjamin, Shreyaskumar Patel, Neeta Somaiah, Anthony Paul Conley, Cynthia E. Herzog, Funda Meric-Bernstam, Vivek Subbiah
Journal: Journal of Clinical Oncology (2016)

11046 Background: There are currently no FDA approved targeted therapies for sarcomas except GIST. Complicating this is the extreme diversity, heterogeneity, and rarity of these neoplasms. Few therapeutic options exist for relapsed and refractory sarcomas. In clinical practice many oncologists refer patients for genomic profiling hoping for guidance on treatment options after standard therapy. We analyzed clinical next generation exome sequencing (NGS) results in patients with advanced sarcomas to discover potentially actionable aberrations and their frequency in a clinical setting. Methods: We reviewed charts of patients with advanced sarcoma referred to investigational cancer therapeutics department and had CLIA certified comprehensive genomic profiling of 200- 315 cancer genes in at least 50ng of DNA. Actionable aberrations were defined as those identifying anti-cancer drugs on the market, in registered clinical trials, or in the Drug-Gene Interaction Database. Results: Among the 98 patients analyzed median age was 33.5 years (range 10-76), M: F ratio 47:51. Common sarcoma types were de-differentiated lipo (N = 20; 20%), leiomyo (n = 11; 11%), osteo (n = 9; 9%), well-differentiated lipo (n = 7; 7%), rhabdomyo (n = 6; 6%), carcino, GIST, spindle cell, and unclassified (N = 5 each; 5%). Seventy percent (69/98) of patients had > 1 potentially actionable genomic aberration. The most common aberrations involved CDK4 amplification (n = 22; 22%), CDKN2A/B loss or mutation (n = 16; 16 %), and MDM2 amplification (n = 21; 21%, non-liposarcoma = 4),. Other notably targetable mutations occurring more rarely included PIK3CA, NOTCH2, NTRK1/3, KDR and PDGFR. Novel fusions were characterized (KIAA1549:BRAF and DCTN1-ALK) that molecularly matched to therapy with patient benefit. Interesting cases included a patient with 3 EWS rearrangements (EWSR1-FLI1, CENPP-EWSR1, ETS1-EWSR1) and re-classification of an unclassified sarcoma to Ewing’s. Conclusions: Incorporating NGS into sarcoma management may allow for more precise diagnosis and sub-classification of this diverse and rare disease. Matching patients to inhibitors targeting CDK, MDM2, PIK3CA, NOTCH2, and NTRK available in basket clinical trials are opportunities for translation of biology into clinical benefit.
Hyperprogressive disease (HPD) in early-phase immunotherapy (IO) trials.
Authors: Yada Kanjanapan, Daphne Day, Lisa Wang, Aaron Richard Hansen, Albiruni Ryan Abdul Razak, Anna Spreafico, Natasha B. Leighl, Anthony M. Joshua, Marcus O. Butler, David Hogg, Lillian L. Siu, Philippe L. Bedard
Journal: Journal of Clinical Oncology (2018)

3063 Background: A subset of patients (pts) treated with immune checkpoint inhibitors experience an accelerated tumor growth rate (TGR) compared with pre-treatment kinetics, known as hyperprogression. The aim of this study was to explore the relationship between HPD, treatment-related toxicity and clinical factors. Methods: Consecutive pts enrolled in early-phase trials involving checkpoint inhibitors and/or costimulatory molecules at Princess Margaret Cancer Centre between 8/2012 – 9/2016 with CT scans available for RECIST 1.1 assessment in the pre-IO treatment (reference, REF) and post-IO treatment (experimental, EXP) periods were reviewed. HPD was defined as RECIST progression at the first on-treatment scan and ≥2-fold increase in TGR between EXP and REF periods. Pts who had prior IO were excluded. Treatment-related toxicities requiring systemic corticosteroids, hormone replacement, IO delay or cessation were considered clinically significant adverse events (CSAEs). Results: 182/352 pts were eligible for analysis. Median age was 61, 54% were male and ECOG performance status (PS) 0 (32%)/1 (68%). Tumor types were head and neck (18%), gynecological (16%), lung (15%), gastrointestinal (15%), genitourinary (12%), melanoma (8%), sarcoma (7%), endocrine (5%) and breast (4%) cancers. Median prior lines of therapy was 1 (range 0 – 7). Royal Marsden Hospital (RMH) prognostic score was 2 or 3 in 59% of pts. 146 pts (80%) received IO monotherapy. IO agents included checkpoint inhibitors in 97% and/or co-stimulatory molecules in 10% of pts. 13/182 (7%) had HPD, with TGR EXP 2-14 folds greater than TGR REF. CSAEs occurred in 20% of pts and was not associated with HPD. There was also no association between HPD and age, PS, tumor type, RMH prognostic score or use of single agent vs combination IO. Median follow-up was 8.4 months. One-year survival was 57% in HPD and 53% in non-HPD pts; with no significant differences in survival adjusted for RMH score between the 2 groups (HR 0.75, 95% CI 0.32 – 1.76, p = 0.5). Conclusions: We observed a 7% rate of HPD within a range of solid tumors treated IO, comparable to other reports. There was no association between HPD and CSAEs, age, tumour type or type of IO therapy. Further studies are needed to identify predictors of HPD.
CDKN2A copy number loss in HPV- and HPV+ head and neck cancer to indicate poor prognosis: An integrated genomic and clinical TCGA analysis.
Authors: William S. Chen, Ranjit Bindra, Allen Mo, Thomas Hayman, Zain Husain, Joseph N. Contessa, Stephen G. Gaffney, Jeffrey P. Townsend, James B. Yu
Journal: Journal of Clinical Oncology (2017)

6060 Background: HPV infection is associated with high p16 expression and relatively good prognosis in head and neck cancers. Analysis of CDKN2A, the gene that encodes the p16 tumor suppressor protein, may further elucidate the association between HPV status and prognosis in head and neck squamous cell carcinomas (HNSCCs). We aimed to identify whether CDKN2A copy number loss was associated with poor survival in HNSCCs stratified by HPV status. Methods: We analyzed The Cancer Genome Atlas (TCGA) head and neck cancer data, integrating genomic measurements with clinical metadata. Patients 85 years old or younger with a primary tumor in the oral cavity, oropharynx, hypopharynx, or larynx were included. Defining CDKN2A copy number loss as a relative log2 copy number ratio &lt; −0.6, CDKN2A mRNA and p16 protein expression levels were compared to confirm significant differences in gene transcription and translation between the copy number loss and non-copy number loss patient groups. Overall survival (OS) and disease-free survival (DFS) were evaluated to characterize prognostic differences between genomic groups. Results: 397 patients negative for HPV (HPV−) and 91 patients positive for HPV (HPV+) HNSCC were identified. 139 HPV− patients and 9 HPV+ patients demonstrated CDKN2A copy number loss. The CDKN2A copy number loss group expressed significantly lower levels of CDKN2A mRNA and p16 protein than did the non-copy number loss group in both HPV+ and HPV− disease. Median OS for HPV− patients with and without CDKN2A copy number loss was 21.8 months and 46.0 months (P = 0.02). Median DFS was 12.0 and 19.4 months respectively (P &lt; 0.05). Median OS for HPV+ patients with and without CDKN2A copy number loss was 12.7 months and 57.4 months (P = 0.004) and median DFS was 7.0 and 36.6 months respectively (P = 0.02). Conclusions: CDKN2A copy number loss was associated with low CDKN2A mRNA and p16 protein expression, with poor prognosis in terms of disease-free and overall survival.