tbuckley/cabot-search huggingface dataset:
Profile of metastatic breast carcinoma: Single center experience from a developing country.
Authors: Manish Sharma, Ajay Gogia, S. V. S. Deo, Nootan Kumar Shukla, Sanjay Thulkar, Rakesh Kumar, Dayanand Sharma, Prabhat Singh Malik, Sushma Bhatnagar, Sandeep Mathur
Journal: Journal of Clinical Oncology (2018)

e13102 Background: Around 5-10 % patients presents with upfront metastasis & 20 -30% patients develop metastasis during follow up. Till date, little is known about pattern and profile of patients with metastatic breast cancer (MBC) from developing countries. Methods: We performed an ambispective review of 484 patients between 1st July 2013 to 31st January 2018, regarding demographic profile, clinical presentation, pathological characteristics, base line biomarker [estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor (HER2/neu)] and the change in biomarker at the time of relapse. Data was analyzed by STATA version 13. Results: A total 1125 patients were registered in our clinic, out of them 294 presented as upfront metastasis (26.5%) and in remaining 190 (22%) patients developed metastasis on follow up.The median time to develop metastasis was 26 (IQR 14 - 50) months. Base line clinical TNM stage was 3.1% stage I, 35.2% stage II, 52.5% stage III. Median age was 49 (range 22-80) years and median duration of symptoms was 6(IQR 3-12) months. Baseline biomarker status was 43% ER/PR positive, 14.3% ER/PR/HER2/neu positive, 15.3% HER2/neu positive and 27.4 % were triple negative breast cancer (TNBC). Discrepancy of hormone status (change at the time of metastasis) was present in 23.7% in ER, 28.9% in PR and 14.7 % in HER2/neu receptor respectively. Single site of metastasis was present in 37.9 % (bone 18.6%, lung 8.2%, liver 4.7%, non-regional lymph node 3.9% and brain 1.6%). More than one site of metastasis was present in 62.1%. Conclusions: This is the first comprehensive study of MBC from India. Most of our patients present late and in advanced stage. Biomarker studies suggest that there is more number of HER2/neu positive and TNBC patients and one third patients had change in receptor status at the time of metastasis.
POSNOC: Positive Sentinel Node—Adjuvant therapy alone versus adjuvant therapy plus clearance or axillary radiotherapy.
Authors: Amit Goyal, Bruce Mann, Alastair Mark Thompson
Journal: Journal of Clinical Oncology (2018)

TPS600 Background: Role of additional axillary treatment (AxT) (axillary lymph node dissection (ALND) or axillary radiotherapy (ART)) in women with macrometastases and undergoing systemic therapy remains unclear. Z11 included both micro and macrometastases (around 40% micrometastases) and showed that ALND may be omitted in women with ≤2 positive nodes undergoing breast conserving surgery (BCS) and receiving whole breast RT. Paradoxically, MA20, demonstrated improved DFS following the addition of regional RT. 51.8% (949/1832) had 1 or 2 positive nodes. 98.9% (1812/1832) had T1/T2 tumors. A post Z11 survey shows that most US oncologists treat the undissected axilla in women with macrometastases with ART rather than omitting AxT. Therefore, a confirmatory study is needed to clarify the role of additional AxT in women with ≤2 macrometastases undergoing BCS and other subgroups that were not included in Z11 e.g. mastectomy, extranodal invasion and sentinel node biopsy (SNB) before NACT. Methods: Primary objective is to assess whether for women with ≤2 macrometastases at SNB, systemic therapy alone is non inferior to systemic therapy plus AxT in terms of axillary recurrence at 5 years. Secondary objectives are arm morbidity assessed by LBCQ and QuickDASH questionnaires; QoL assessed by FACT B+4 questionnaire; anxiety assessed by STAI; locoregional recurrence; distant metastasis; time to axillary recurrence; axillary recurrence free survival; DFS; OS; contralateral breast cancer; non breast malignancy; economic evaluation. Eligibility criteria are: ≥18 y, uni or multifocal invasive cancer, T1/T2, 1 or 2 macrometastases, with or without extranodal invasion. Target sample size is 1900 with a projected drop out and non compliance with treatment allocation rate of 10%. Primary analysis will be per protocol. Following pre specified subgroup analyses shall be performed: number of macrometastases, age (50, ≥50), type of breast surgery, ER status, tumour grade (1 or 2, 3), SN assessment technique (OSNA, non OSNA), extranodal invasion. POSNOC opened to recruitment in July 2014. To date 960 women have been recruited at 82 sites in the UK and 18 sites in Australia and New Zealand. Clinical trial information: NCT02401685.
Characteristics of patients (pts) receiving end of life treatment (EOLT) at an NCI-Designated Cancer Center.
Authors: Kevin Do, Sarmad Sadeghi, Peggy Matsuura, Gwendoyn Lynch, Afsaneh Barzi
Journal: Journal of Clinical Oncology (2017)

e18245 Background: End of life treatment is identified as a high cost low return intervention and is under evaluation as a quality measure for providers. A 2012 ASCO expert panel acknowledged it as the most wasteful practice in oncology. However, characteristics of pts who receive EOLT is poorly described and so interventions to assist providers avoid such treatments are limited. Methods: We identified 299 pts with cancer diagnosis from 2008-2012 and confirmed deceased using our cancer registry. Pts charts were reviewed for last cancer-specific treatments, either chemotherapy (CTX) or radiation therapy (XRT). Characteristics of pts who received treatment within the last 90, 30, and 14 days of life was described. We compared the characteristics of those who received treatment with in the last 14 days of life (here defined as EOLT) to the rest of the population. Chi-squared tests were used to compare between groups. Results: 292 pts (98%) received CTX or XRT within the last 90 days of life, 167 (56%) received treatment within the last 30 days, and 78 (26%) within the last 14 days of life. The main modality of EOLT was CTX (99%). By cancer subtype, up to 50% of gastric and renal cell carcinoma patient received treatment in the last 14 days of life. Older pts, those on clinical trials, and those with longer period of time between diagnosis and death, were less likely to receive EOLT. There is a trend for receipt of EOLT for female pts and those younger than 65 years (p-value 0.059) Conclusions: Our data establishes that more than 25% of deceased pts received treatment in the last 14 days of life. Certain characteristics may influence providers to be aggressive and to deliver care when it is futile. Research to risk stratify pts who are good candidates for treatment is necessary and can improve the value of care delivered to these subjects.
Theoretical model and clinical validation of blood tumor mutation burden (bTMB) detection for cancer immunotherapy.
Authors: Jianchun Duan, Zhijie Wang, Jing Lu, Hua Bai, Rui Wan, Shuhang Wang, Jiachen Xu, Xinkai Cao, Hua Dong, Tongfu Xu, Shangli Cai, Fu-Gen Li, Jie Wang
Journal: Journal of Clinical Oncology (2018)

12034 Background: Tumor mutational burden(TMB) measured by whole exome sequencing (WES) or cancer gene panel (CGP) sequencing, has been identified to be associated with clinical outcome to anti-PD1/PDL1 treatment. However, a considerable proportion of patients(pts) with advanced lung cancer cannot acquire enough tumor tissue for TMB detection. Here, we defined an optimal gene panel for TMB estimation and validated the availability of blood TMB (bTMB) from circulating tumor DNA (ctDNA) in predicting therapeutic efficacy of anti-PD1/PDL1. Methods: A theoretical model of measuring TMB by CGP was established including 9205 WES-measured samples of 33 tumor types based on TCGA database. We further designed a panel (CT150) including 62 hotspot genes and 88 lung-cancer related genes, and built a robust bTMB detection pipeline. Correlation of CT150-measured bTMB and WES-measured TMB from paired tumor tissue in 30 NSCLC patients was analyzed to validate our model. Public clinical dataset and an independent clinical cohort were used to evaluate the association of bTMB with the efficacy of anti-PD1/PDL1 treatment. Results: Our model demonstrated that at least 100 genes need to be included in CGP when estimating WES based TMB, which was identified being influenced by the choice of hotspot genes, the weight of nonsynonymous mutations and the sequencing depth. In most tumor types, the CT150-measured TMB is highly correlated with WES-measured TMB. The bTMB and WES-based tumor TMB (tTMB) in 30 NSCLC patients is highly correlated. pts with high TMB estimated by CT150 had a significantly longer median progression free survival (mPFS) (14.5 vs 4.1 months, p = 0.01) than those with low TMB in the published Rizvi cohort (N = 34) . In a pilot study of 12 NSCLC pts treated with PD1/PDL1 inhibitors, pts with bTMB-high (designated as≥8 muts) had higher durable clinical benefit (DCB) rate and longer mPFS than those of bTMB-low (DCB %: 100% vs 42.9%, mPFS: 9.9 vs 2.9 months, p = 0.03). Conclusions: The designed CT150 panel can be utilized to estimate the TMB in the majority of cancer types. The bTMB estimated by this panel might provide a noninvasive biomarker assay to identify NSCLC pts benefitting from PD1/PDL1 inhibitors.
Variability in the extent of del(5q) and its clinical implication in myelodysplastic syndromes (MDS).
Authors: Zuzana Zemanova, Jana Brezinova, Karla Svobodova, Halka Lhotska, Silvia Izakova, Iveta Sarova, Libuse Lizcova, Sarka Ransdorfova, Lenka Pavlistova, Monika Belickova, Magda Siskova, Radana Neuwirtova, Jaroslav Cermak, Tomas Stopka, Anna Jonasova, Kyra Michalova
Journal: Journal of Clinical Oncology (2018)

e19025 Background: The interstitial deletion of the long arm of chromosome 5—del(5q)—is the most common cytogenetic abnormality in MDS occurring either as a sole aberration or as a part of complex karyotypes (CK). MDS with isolated del(5q) are associated with a favorable outcome while MDS with CK relate to poor prognosis. Extent of deleted segment is highly variable. However, it remains unclear whether its size matters for the different MDS phenotypes. The aim was to compare the extent of deletion in 226 MDS patients [78 with isolated del(5q) and 148 with del(5q) involved in CK] and to assess the relationship of del(5q) extent and TP53 gene mutation. Methods: Extent of del(5q) was analyzed using I-FISH (Abbott), mBAND (MetaSystems) and array CGH/SNP (CytoChip Cancer SNP 180K, Illumina or SurePrint G3 Cancer CGH+SNP 4x180K, Agilent). Sequence analysis of TP53 gene was performed in 84 cases using amplicon deep sequencing (exons 4–11) on a 454 GS Junior system (Roche) or with TruSight Myeloid Panel Kit on MiSeq sequencing instruments (Illumina). Results: In the group with isolated del(5q), the most frequently deleted segment ranged between the bands 5q14 and 5q33.3, with the smallest deletion encompassing the 5q31.1-5q31.3 region (18.527 Mb). The TP53 mutation was proved in 19.4% cases. The size of the deletion did not significantly differ in patients with and without TP53 mutation. In the group with CK, the deletion often involved entire long arm including the telomeric region. In this group, the mutation of TP53 and/or LOH17p was detected in 49% of patients. The CDRs were located at the region 5q31.1 (5.522 Mb) in cases with isolated del(5q) and between the bands 5q31.1 and 5q31.3 (18.527 Mb) in patients with CK. Conclusions: Patients with isolated del(5q) had a smaller size of the deleted segment. More extensive 5q deletion was associated with higher karyotype complexity, increased frequency of TP53 aberrations and worse prognosis. Accurate analysis of breakpoints and range of del(5q) points out to the correlation of deletion size with increasing genomic instability in MDS and contributes to a better understanding of the MDS pathogenesis. Supported by RVO-VFN64165, GACR P302/12/G157, ProgresQ28/LF1, MHCR 00023736.
Cochrane HPV vaccine review: BMJ journal defends “inconvenient criticisms”
Authors: Nigel Hawkes
Journal: BMJ (2018)

Journals shouldn’t shrink from offering criticisms that may be considered inconvenient, say the editors of a BMJ journal in the latest round of a dispute over the quality of a Cochrane review.

Carl Heneghan and Igho Onakpoya, editors of BMJ Evidence-Based Medicine , make no apology for having published a paper that criticised the conduct of an important Cochrane review of vaccines for human papilloma virus,12 which have been widely adopted around the world to protect against cervical cancer.

The criticisms, which included the claim that 20 studies were not …
Herpes zoster vaccine and varicella zoster virus infection among cancer patients having chemotherapy.
Authors: Lisa Y. Law, Diane M. Carpenter, Laura M. Grigor, Bijay P. Nair
Journal: Journal of Clinical Oncology (2018)

1563 Background: Varicella zoster virus (VZV) infection is an opportunistic infection among immunocompromised patients. The herpes zoster (HZ) vaccine is a live vaccine not approved for administration to oncology patients receiving chemotherapy. We aimed to assess the association between HZ vaccine given prior to cancer diagnosis and VZV infection in this population. Methods: In this retrospective cohort study conducted in Kaiser Permanente Northern California (KPNC) we assessed the association between prior HZ vaccination and VZV infection in cancer patients age 60-89 years having chemotherapy January 1, 2010-December 31, 2014. Subjects were followed until death, loss of membership, or end of study (December 31, 2016). Multivariable analyses were performed using adjusted relative risk models. Variables controlled for included age, sex, hematological vs. non-hematological cancers, high dose steroid therapy, prior immunomodulation therapy, and antiviral prophylaxis. Subanalyses were performed for subjects with and without hematological cancers. Results: Our study consisted of 13,069 subjects having cancer and chemotherapy; of these 5090 (39.9%) had prior administration of the HZ vaccine. Median follow-up time was 26.0 months (IQR: 10.6-42.9). Of vaccinated subjects 198 (3.9%) developed VZV infection compared to 410 (5.1%) of unvaccinated subjects (Adjusted Relative Risk [ARR] 0.73, 95% CI 0.62-0.86). Hematological cancers were associated with VZV infection (referent: other cancers, ARR 2.76, 95% CI 2.32-3.29); antiviral prophylaxis was not (ARR 1.00, 95% CI 0.72-1.40). In subanalyses the HZ vaccine was more protective against VZV infection in subjects with hematological cancers (ARR 0.62, 95% CI 0.47 – 0.83) than in those with other cancers (ARR 0.81, 95% 0.66-0.99). There were 7965 deaths (60.9%) during follow-up. The HZ vaccine was protective against all-cause mortality in all subjects (ARR 0.76, 95% 0.74-0.79). Conclusions: The live HZ vaccine is protective against VZV infection in oncology patients receiving chemotherapy; this effect is greater in subjects having hematological cancers. The vaccine is also associated with decreased all-cause mortality.
A systematic review examining the relationship between progression-free survival and overall survival in adults with untreated metastatic pancreatic cancer.
Authors: Omar Dabbous, Colin Wight, Louise Crathorne, Ammar Qadan
Journal: Journal of Clinical Oncology (2017)

e15724 Background: The majority of pancreatic cancers are diagnosed in advanced stages with a median survival of 3 to 5 months. From 2005 to 2012, the US Food and Drug Administration approved 41 oncology drugs; surrogate endpoints were used in 84% of the trials providing the basis of approval. The aim of this systematic review was to evaluate the relationship between PFS/TTP and OS in metastatic pancreatic cancer. Methods: A systematic literature review used the Centre for Reviews and Dissemination principles to identify studies that reported median PFS or TTP and OS. We searched Medline, Medline In-Process, and Embase, with the following additional limits: English language and published 1/1990 to 7/ 2016. Selection criteria, defined a priori, included chemo, immuno or targeted therapy, randomized controlled studies (Phase 2 or 3) in patients with metastatic pancreatic cancer. Studies were assessed for quality using the Cochrane Risk of Bias tool and the Jadad scale. Studies were excluded if full-text articles were not available, and if patients received chemotherapy plus radiotherapy or surgery. Correlation analyses and weighted linear regression were used to assess the association between median PFS/TTP and median OS. The distributions of median PFS/TTP and OS were examined using scatterplots. Results: 1,691 studies were identified. After screening by title and abstract, 212 full articles were assessed, of which 28 studies (evaluating 6,734 patients) met the selection criteria. The mean median PFS/TTP and OS were, respectively, 3.82 months (range 1.2 to 6.8 months), and 7.06 months (range 2.5 to 11.9 months). The correlation coefficient was 0.837; 95% CI (0.734-0.903) indicating a very strong positive correlation between median OS and median PFS/TTP. Regression analysis indicated that median PFS/TTP was a highly significant predictor of median OS = 2.177 + 1.247 * median PFS/TTP (p &lt; 0.001). Conclusions: The analysis demonstrates a very strong positive correlation of median PFS/TTP with median OS for the treatment of metastatic pancreatic cancer, which reinforces the hypothesis that PFS or TTP is a useful surrogate endpoint for OS in this cancer setting.
Peter John Bowers
Authors: Anna Kushlick, Sue Bailey
Journal: BMJ (2018)

Peter John Bowers was born in Sunderland, the son of Arthur Clifford Bowers (a general practitioner, who died in 1947) and Doris Bowers. As a child, Peter excelled in both science and arts, while attending Queen Elizabeth Grammar School. His passion and love for learning, and for generously sharing his knowledge, together with his humanity, integrity, and eloquence, were his drivers throughout life.

He already held a degree in chemistry from the University of London when he graduated from Manchester University Medical School in 1973 with double honours. He remained in the north west to complete all postgraduate training in paediatrics, psychiatry, and then higher specialist training in child and adolescent psychiatry; he was clinical tutor from 1981 to 1983.

Peter Bowers spent his entire consultant career (1983-2008) as an NHS consultant in child and adolescent psychiatry across Tameside and Glossop …
A sequential cohort study of combination immunotherapy with BN-brachyury vaccine, M7824, ALT-803 and epacadostat in metastatic castration-resistant prostate cancer (mCRPC) (QuEST1).
Authors: Jason M. Redman, Seth M. Steinberg, James L. Gulley
Journal: Journal of Clinical Oncology (2018)

TPS3130 Background: Vaccine and checkpoint inhibitor monotherapies infrequently produce objective responses in mCRPC. Combination immunotherapy that 1) facilitates immune recognition of tumor, 2) increases number and function of tumor directed effector cells, and 3) decreases immune suppression in the tumor microenvironment (TME), is a promising strategy to improve outcomes in mCRPC. In pursuit of safety and efficacy, this Quick Efficacy Seeking Trial (QuEST1) will add immunotherapies to sequential study arms. QuEST1 first combines the BN-Brachyury vaccine, targeting a transcription factor involved in epithelial-mesenchymal transition and drug resistance, with a bifunctional agent (M7824) targeting PD-L1 and TGF-β. The next arm adds an IL-15 superagonist (ALT-803) to boost NK and T cell number and function. The final arm adds epacadostat, an IDO1 inhibitor that dampens immune suppression in the TME. Methods: Eligibility criteria: prostate cancer, castrate testosterone level, and metastases to bone, organs or lymph nodes. Exclusion criteria: ECOG > 1, immunosuppression, and regular use of narcotic analgesics. QuEST1 will enroll up to 93 patients to sequential arms; each arm evaluates 2-4 treatments. A safety cohort, open to any solid tumor, will assess safety and dose finding for M7824 + ALT-803 (enrolls simultaneously to Arm1). Arm1 will treat 13 pts with BN-Brachyury + M7824. If safety, Arm2 (adds ALT-803) will enroll 13 pts. If safety, Arm3 (adds epacadostat) will enroll 13 pts. Primary endpoints (response definition): objective response by RECISTv1.1 and/or sustained decrease in PSA ≥30% (treatment efficacy). Using a Simon minimax two stage design, if ≥2 of 13 patients in an arm demonstrate efficacy, the arm will expand to n = 25. The fraction of patients who experience efficacy will be reported with two-sided 80% and 95% confidence intervals. Secondary endpoint: PFS. Exploratory endpoints: Correlate immunologic parameters with response (number/function of circulating antigen-specific T cells, immune cell phenotype, sCD40L, sCD20, prostate-specific membrane antigen+ extracellular vesicles (EV) and immune EVs.
Characteristics of adult multiple myeloma patients receiving carfilzomib in a U.S. community oncology setting.
Authors: Robert M. Rifkin, Rohan Medhekar, Khalid Mezzi, Kathleen Aguilar, Thomas Wilson, E. Susan Amirian, Sumeet Panjabi
Journal: Journal of Clinical Oncology (2017)

e19517 Background: Carfilzomib (K) is indicated for treatment of relapsed or refractory multiple myeloma (MM). We studied the characteristics of patients receiving K in the US Oncology Network’s (USON) EHR database. Methods: Patients ≥18 years who received a K-containing regimen between 11/01/2013-02/29/2016, were not in a clinical trial, and had ≥2 visits at a USON clinic were eligible. Baseline characteristics were compared between patients who received a K-based doublet, triplet or other regimen (monotherapy or &gt;3 treatments). Results: Of the 718 patients who received a K-based regimen during the study period, 219 (30.5%) had doublet regimens, 287 (40.0%) received triplet regimens and 212 (29.5%) received other regimens; 494 (68.8%) received regimens with ≥3 therapies. Mean age was 69.7 and 64.7 years among patients on doublets and triplets, respectively. A higher proportion of female patients received doublets (53.0%) (Table). There were no differences in ISS stage or number of comorbidities across patients receiving doublets, triplets, or other regimens. Conclusions: In this real-world analysis of K-regimens, a majority of patients received triplet regimens. Older patients received doublet regimens more frequently. The influence of regimen on outcomes controlling for patient characteristics and prior treatments among MM patients receiving K-based regimens should be studied. [Table: see text]