tbuckley/cabot-search huggingface dataset:
Docetaxel dose-intensity effect on overall survival in patients with metastatic castrate-sensitive prostate cancer.
Authors: Igal Kushnir, Ranjeeta Mallick, Michael Ong, Christina Canil, Dominick Bossé, Kim Koczka, M. Neil Reaume
Journal: Journal of Clinical Oncology (2019)

e16501 Background: Several studies assessed the association of docetaxel dose intensity (DI) and efficacy in metastatic castrate-resistant prostate cancer (mCRPC) patients with contradicting conclusions. In this retrospective analysis we will assess whether the docetaxel DI used in patients with metastatic castrate-sensitive prostate cancer (mCSPC) is associated with overall survival (OS). Methods: We have identified all the patients with mCSPC treated at The Ottawa Hospital Cancer Centre that received docetaxel chemotherapy between June 2014 - September 2017. For each patient we calculated the relative dose intensity (RDI) and assessed whether it’s associated with OS using univariate and multivariate cox-proportional hazards analysis. Results: Eighty-0ne patients were included in the analysis. Nineteen patients (23.5%) had their body surface area capped at 2 which resulted with de facto median dose reduction of 7% (IQR 6% - 9%). Ten patients had upfront dose reduction (usually due to significant co-morbidities) with a median dose reduction of 20% (IQR 19.25 – 20.75). Only 35 patients (43.2%) were able to complete the planned treatment with a RDI of at least 90%. After a median follow-up of 29.4 months, 32 patients (39.5%) died. The median OS was 43.9 months. On a univariate analysis RDI and number of cycles of docetaxel received were found to be statistically significant associated with OS. For every 10% decrease in RDI the risk of death increased by 23% (HR 1.23, 95% CI 1.09 – 1.4, P = 0.0011). For every incremental cycle (up to a total of 6) the risk of death decreased by 27% (HR 0.73, 95% CI 0.61- 0.88, P = 0.001). On multivariate analysis we included age, Gleason score, burden of disease, visceral involvement and baseline PSA. Reduced RDI remained the only significant variable associated with OS (HR 1.2, 95% CI 1.04 – 1.39, P = 0.0117). Conclusions: Reduced docetaxel DI administrated to mCSPC patients is associated with worse survival. Therefore unnecessary docetaxel dose reductions, treatments delays and early discontinuation should be avoided. Granulocyte-colony stimulating factor should be considered in order help maintain standard DI.
Stereotactic body radiotherapy (SBRT) for colorectal liver metastasis: Clinical outcomes from the international multi-institutional RSSearch Patient Registry.
Authors: Pollyanna D'Avila Leite, Andrew M. Gaya, Rachelle Marie Lanciano, Jun J. Yang, Oliver Blanck, Robert Urwin, Joanne N. Davis, Anand Mahadevan
Journal: Journal of Clinical Oncology (2019)

e15040 Background: We investigated factors associated with clinical outcome for liver metastases from colorectal primary tumors treated with Stereotactic Body Radiotherapy (SBRT) from a multi-center, international, prospective patient registry. Methods: A subgroup of patients with colorectal liver metastases treated with SBRT was identified from the RSSearch Patient Registry. Patient, tumor and treatment characteristics associated with outcome were evaluated. Dose fractionations were normalized to BED10. Overall survival (OS) and local control (LC) were evaluated using Kaplan Meier analysis and log-rank test. Results: 217 patients with 233 liver metastases from primary colorectal cancer treated with SBRT between 2005-2017 and enrolled in the RSSearch Patient Registry were included. The median follow-up was 15 months (1–75 months). 77% of patients received prior or concurrent chemotherapy. Median tumor volume was 21.95 cm3 (0.5 – 638 cc), median SBRT dose was 45 Gy (16 – 60 Gy) delivered in a median of 3 fractions (1-5). Median number of liver metastases was 1 (1-8). Median overall survival (OS) was 27 months; median local control (LC) was 41 months. One and two-year OS was 75% and 55%, respectively. One and two-year LC was 75% and 66%, respectively. Higher BED10 was associated with improved LC with median LC of 44 months for BED10 ≥ 100 Gy vs 39 months for BED10 &lt; 100 Gy (p = 0.0007). Higher BED10 was also associated with improved OS: median of 33 months for BED10 ≥ 100 Gy vs to 18 months for BED10 &lt; 100 Gy (p = 0.0009). Smaller tumor volume was associated with improved OS: median OS of tumor volume was 34 months for tumors &lt; 20 cc vs 20 months for tumors ≥ 22cc (p = 0.0037). Local control was not significantly associated with tumor volume: median LC for tumor &lt; 22 cc vs ≥ 22cc was 44 months vs 39 months, respectively (p = 0.193). Age, prior or current chemotherapy and BMI were not associated with OS or LC. Conclusions: In this multi-institutional prospective cohort, OS and LC were favorably correlated with small tumor volume and higher BED10.
Observing Ramadan and sleep-wake patterns in athletes: a systematic review, meta-analysis and meta-regression
Authors: Khaled Trabelsi, Nicola Bragazzi, Sahar Zlitni, Aimen Khacharem, Omar Boukhris, Kais El-Abed, Achraf Ammar, Saber Khanfir, Roy J Shephard, Ahmed Hakim, Wassim Moalla, Hamdi Chtourou
Journal: British Journal of Sports Medicine (2019)

Objective To evaluate the effect of observing Ramadan on athletes’ sleep patterns. Design Systematic review and meta-analysis. Data sources The entire content of PubMed/MEDLINE and Web of Science. Eligibility criteria for selecting studies Single-group, prepost and cross-over design studies conducted in athletes aged ≥18 years, training at least twice a week and published in English before 12 July 2018 were included. Studies assessing sleep quantity, quality, daytime sleepiness and/or daily naps based on objective or subjective methods were deemed eligible. Study appraisal The methodological quality was assessed using ‘QualSyst’. Results Of 13 selected articles, 7 were of strong quality, 3 were moderate and 3 were weak. 11 studies evaluated total sleep time (TST); this decreased during Ramadan in 4 studies, increased in 1 and remained unchanged in 6. Pooled TST findings indicated a moderate effect size (− 0.97, SE=0.37, 95% CI −1.69 to −0.25, t=−2.64, p=0.01) with significant heterogeneity but no publication bias. Meta-regressions showed no effects of study year, age, sample size, type of sport or competition level, but there were effects of country (with France and Tunisia being the most affected countries and Turkey the least affected, Q=32.14, p&lt;0.0001) and study design (Q=7.74, p=0.02). Four studies measured self-reported sleep quality and it decreased in three studies. One study of sleep architecture reported more frequent waking and more light sleep during Ramadan. Daily nap duration was increased in two studies, but daytime sleepiness remained unchanged in four studies. Conclusion When athletes continue to train at least two times/week while observing Ramadan, TST is decreased compared with athletes’ baseline levels.
Efficacy and safety of immune checkpoint inhibitors in elderly patients (≥70 years) with squamous cell carcinoma of the head and neck.
Authors: Caroline Even, Nicolas Martin, Edith Borcoman, Anne Auperin, Nouritza Torossian, Neus Baste, Joel Guigay, Christophe Le Tourneau, Esma Saada, Amaury Daste, Khalil Saleh
Journal: Journal of Clinical Oncology (2019)

6035 Background: Recent meta-analysis showed that immune checkpoint inhibitors (ICI) have comparable activity in younger vs older patients (pts) (≥65 years (y)). However little is known about efficacy and safety of ICI in elderly pts with relapsed/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). The aim of this study is to compare efficacy and grade ≥3 immune-related adverse events (irAEs) of ICI in pts ≥70 y with R/M SCCHN to younger pts. Methods: A retrospective study was conducted at 4 French hospitals. Eligibility criteria were pts treated with ICI for R/M SCCHN between September 2014 and December 2018. Clinical and radiological data and outcome were collected from review of medical records. Results: Two hundred twenty six pts were enrolled including 67 pts ≥ 70 y. Median age of elderly pts was 75y (range 70-87). Elderly pts received ICI as first-line treatment in 21% of pts vs 17% in younger pts. In elderly pts, 9% had ECOG of 0, 72% had ECOG of 1 and 15% had ECOG of 2 at ICI initiation vs 34%, 62% and 4% respectively in younger pts (p = 0.0006). In elderly pts, 22% had only loco-regional relapse at ICI initiation, 30% only distant recurrence and 49% had both vs 42%, 32% and 26% respectively (p = 0.0014). Elderly pts received ICI as monotherapy in 73% of pts vs 52% (p = 0.0027). The ORR in elderly pts was 23% vs 13% in younger pts (p = 0.071). After a median follow-up of 16.8 months (m) (range 10.7-23.7), median OS was 9.7m in elderly pts vs 8.7m in younger pts (p = 0.87). Median PFS was 2.7 m in elderly pts vs 1.9 m (p = 0.2). After adjustment for ECOG, type of evolution, number of ICI drugs, time between initial diagnosis and ICI start and number of previous lines, age ≥70 years was significantly associated with a better PFS (HR = 0.66 (95%CI = 0.47;0.93), p = 0.02) but was not significantly associated with OS (HR = 0.91 (95%CI = 0.61;1.34), p = 0.62). Grade ≥3 irAEs occurred in 15% of elderly pts vs 8% of younger pts (p = 0.13). Patients with grade ≥3 irAEs had a significantly higher ORR than pts without Grade ≥3 irAEs (36% vs 14%, p = 0.007). Conclusions: Elderly pts treated with ICI had significantly higher PFS but not OS after adjustment. Grade ≥3 irAEs were associated with significantly higher ORR to ICI in the whole population.
Real-world large-scale study of <i>ERBB2</i> gene fusions and its response to afatinib in Chinese non-small cell lung cancer (NSCLC): A multicenter study.
Authors: Chunwei Xu, Wen xian Wang, Quxia Zhang, Yu Chen, Xiuyu Cai, Yong Fang, You-cai Zhu, Yun-jian Huang, Hong Wang, Wu Zhuang, Yinbin Zhang, Liping Wang, Xiaofang Jiang, Shangli Cai, Jianhui Huang, Shuitu Feng, Meiyu Fang, Gang Chen, Tangfeng Lv, Yong Song
Journal: Journal of Clinical Oncology (2019)

e13002 Background: ERBB2 mutation has been found to be an oncogenic driver gene in non-small cell lung cancers (NSCLC) and ERBB2-directed therapies have shown promising results in this unique population, while little is known about ERBB2 fusion association with outcomes of afatinib. The aim of this study was to investigate the efficacy of afatinib in patients with advanced ERBB2 fusion NSCLC. Methods: A multicenter study in China was initiated from February 2014, and NSCLC patients have been enrolled as of December 2018. To determine the frequency of the ERBB2 fusions in NSCLC and other tumors, we analyzed data from 2743 clinical NSCLC cases, each of which had results from next-generation sequencing (NGS)-based 381 genes panel assay, analogous to the index patient. Results: Of this entire cohort, eight (0.29%) patients were identified with an ERBB2 fusion, including TNS4-ERBB2 (1), ERBB2-CD79B (1), IGFBP4-ERBB2 (1), ERBB2-PSMD3 (1), SEZ6-ERBB2 (1), ERBB2-PGAP3 (1), ARL5C-ERBB2 (1) and B3GNTL1-ERBB2 (1). The genes most frequently co-altered in patients with ERBB2 fusions were TP53 (37.50%), CDKN2A (25.00%), RB1 (25.00%) and RBM10 (25.00%). Overall TMB in the ERBB2 fusions was low (median 2.97 mut/Mb). For treatments, 25.00% patients chose afatinib, another patients chose chemotherapy or chemoradiotherapy, and case examples of advanced ERBB2 fusion driven NSCLC patients responding to afatinib were actively being sought thru our database. Conclusions: Patients with advanced ERBB2 fusion NSCLC showed a good outcome of afatinib compared to those with ALK/ ROS1 fusion which response to crizotinib, which strengthen the need for effective ERBB2-targeted drugs in clinical practice.
Site, age, and gender distribution of extra-gonadal germ cell tumors in the US from 1973 to 2015.
Authors: Elizabeth Pan, Ugonna Ihenacho, Victoria Cortesssis, Syem Barakzai, James S Hu
Journal: Journal of Clinical Oncology (2019)

e16051 Background: Germ cell tumors (GCT) commonly arise in post pubertal gonads where they are influenced by sexually dimorphic hormone signaling. More rarely, extra-gonadal GCTs (EGGCTs) arise in midline sites, coinciding with the route of primordial germ cell migration. EGGCTs are proposed to arise from cells not completing this migration. We characterized the incidence of EGGCTs according to patient and tumor features in an attempt to elucidate tumor origins. Methods: In Surveillance, Epidemiology, and End Results (SEER) Program SEER*Stat Database SEER 9 Regs Research Data, 1973-2015, primary EGGCT cases were identified by ICD-O-3 histologic types (seminoma: 9060-9062, 9064; non-seminoma 9065-9101) grouped into central nervous system (CNS), mediastinum, and other EGGCT sites. Age-specific incidences for males and females were divided into adolescents and young adults (AYA) defined by the National Cancer Institute as 15-39 years of age, and younger childhood and older adult groups. Results: In AYAs and older adults, age-adjusted incidence of males exceeded that of females at all sites (p≤0.006, all comparisons) (Table). Male incidence was highest in AYAs (all EGGCT, 4.35/1,000,000 person-years (Mpy); mediastinum, 2.17/Mpy; other 0.68/Mpy). Female incidence was highest in childhood (CNS, 0.86/Mpy; mediastinum, 0.14/Mpy; other 0.64/Mp-y). Conclusions: Patterns of EGGCT incidence differ substantially between sexes. Permissive extra-gonadal sites of males or male-predominant exposures may explain higher incidence in males. Alternatively, EGGCT precursor cells may have sex-specific features affecting malignant potential. [Table: see text]
Delineating longitudinal patterns of response to neoadjuvant systemic therapy (NAST) in triple-negative breast cancer (TNBC): Profiling results from a randomized, TNBC enrolling trial to confirm molecular profiling improves survival (ARTEMIS; NCT02276443).
Authors: Sahil Seth, Lei Huo, Gaiane M Rauch, Beatriz E Adrada, Helen Piwnica-Worms, Alastair Mark Thompson, Elizabeth A. Mittendorf, Jennifer Keating Litton, William Fraser Symmans, Giulio Francesco Draetta, Andrew Futreal, Stacy L. Moulder, Jeff Chang
Journal: Journal of Clinical Oncology (2019)

586 Background: The heterogeneity of TNBC results in varied responses to NAST: 30-40% of patients (pts) have pathologic complete response (pCR) with excellent prognosis. Those with residual disease, have a much higher risk of recurrence. Longitudinal profiling assesses biologic response to NAST and mechanisms of resistance. Methods: Pts with stage I-III TNBC began a planned 4 cycles of Adriamycin-based chemo (AC). Biopsies were performed pre (mandatory) and post (optional) AC. Volumetric change by ultrasound (VUS) at completion of AC (or progression) was calculated. Pts with sensitive disease received subsequent taxane-based (T) therapy. Pts with insensitive disease were offered phase II trials. Pathologic response was assessed at surgical resection in 47 pts. Matched samples, pre and post AC (N = 48 pts) underwent transcriptomic and genomic profiling. Samples were classified into six previously identified ARTEMIS subtypes of TNBC (ART-Type). Immune deconvolution and estimation was performed using RNA-Seq profiles. Differential pathway-level analysis was performed comparing pre and post AC samples. Results: There was heterogeneity in response to AC with 4 predominate patterns of biologic response (Table). In 48% of cases the ART-Type of the tumor switched after AC, with androgen receptor like (LAR) and immune modulatory (IM) showing greatest stability. Tumors with enrichment in EMT or those with no significant dysregulation after AC (Groups C + D) were associated with less immune modulation and lower rates of pCR compared to those with depleted EMT (A and B) (8.7% vs 45.8%, p = 0.0078). Conclusions: Molecular profiling of longitudinal TNBC samples reveals distinct response patterns in tumors and their micro-environments upon treatment with AC. These patterns were indicative of pathologic response in this cohort; however, they require validation in a separate cohort. Clinical trial information: NCT02276443. [Table: see text]
Efficacy and Toxicity of Pegaspargase and Calaspargase Pegol in Childhood Acute Lymphoblastic Leukemia: Results of DFCI 11-001
Authors: Lynda M. Vrooman, Traci M. Blonquist, Kristen E. Stevenson, Jeffrey G. Supko, Sarah K. Hunt, Sarah M. Cronholm, Victoria Koch, Samantha Kay-Green, Uma H. Athale, Luis A. Clavell, Peter D. Cole, Marian H. Harris, Kara M. Kelly, Caroline Laverdiere, Jean-Marie Leclerc, Bruno Michon, Andrew E. Place, Marshall A. Schorin, Jennifer J. G. Welch, Donna S. Neuberg, Stephen E. Sallan, Lewis B. Silverman
Journal: Journal of Clinical Oncology (2021)

PURPOSE Dana-Farber Cancer Institute Acute Lymphoblastic Leukemia (ALL) Consortium Protocol 11-001 assessed efficacy and toxicity of calaspargase pegol (calaspargase), a novel pegylated asparaginase formulation with longer half-life, compared with the standard formulation pegaspargase. METHODS Patients age 1 to ≤ 21 years with newly diagnosed ALL or lymphoblastic lymphoma were randomly assigned to intravenous pegaspargase or calaspargase, 2,500 IU/m 2 /dose. Patients received one induction dose. Beginning week 7, pegaspargase was administered every 2 week for 15 doses and calaspargase every 3 week for 10 doses (30 weeks). Serum asparaginase activity (SAA) (≥ 0.1 IU/mL considered therapeutic) was assessed 4, 11, 18, and 25 days after the induction dose and before each postinduction dose. RESULTS Between 2012 and 2015, 239 eligible patients enrolled (230 ALL, nine lymphoblastic lymphoma); 120 were assigned to pegaspargase and 119 to calaspargase. After the induction dose, SAA was ≥ 0.1 IU/mL in ≥ 95% of patients on both arms 18 days after dosing. At day 25, more patients had SAA ≥ 0.1 IU/mL with calaspargase (88% v 17%; P ˂ .001). Postinduction, median nadir SAAs were similar (≥ 1.0 IU/mL) for both arms. Of 230 evaluable patients, 99% of pegaspargase and 95% of calaspargase patients achieved complete remission ( P = .12), with no difference in frequency of high end-induction minimal residual disease among evaluable patients with B acute lymphoblastic leukemia (B-ALL). There were no differences in frequencies of asparaginase allergy, pancreatitis, thrombosis, or hyperbilirubinemia. With 5.3 years median follow-up, 5-year event-free survival for pegaspargase was 84.9% (SE ± 3.4%) and 88.1% (± SE 3.0%) for calaspargase ( P = .65). CONCLUSION Every 3-week calaspargase had similar nadir SAA, toxicity, and survival outcomes compared with every 2-week pegaspargase. The high nadir SAA observed for both preparations suggest dosing strategies can be further optimized.
Phase 1/2 dose-escalation and expansion study investigating SAR439859 +/- palbociclib in postmenopausal women with estrogen receptor-positive (ER+)/HER2- metastatic breast cancer.
Authors: Aditya Bardia, Hannah M. Linden, Gary A. Ulaner, Sarat Chandarlapaty, Alice Gosselin, Marina Celanovic, Mario Campone
Journal: Journal of Clinical Oncology (2019)

TPS1105 Background: Endocrine therapy +/- cyclin-dependent kinase 4/6 inhibitors, such as palbociclib, is the standard of care for ER+/HER2- breast cancer. Tumors often become resistant to this combination but retain ER signaling dependence, allowing for sequential ER-directed therapy. Unlike other classes of endocrine therapy with one mode of action, selective ER degraders (SERDs) block signaling by both ER competitive antagonism and degradation, targeting resistance settings that other treatments cannot. SAR439859 is a potent, oral SERD with improved preclinical efficacy and pharmaceutical properties vs other SERDs. This study investigates SAR439859 +/- palbociclib in postmenopausal women with ER+/HER2- metastatic breast cancer. Methods: This prospective, open-label, non-randomized Phase 1/2 study (NCT03284957; TED14856) assesses SAR439859 single agent at dose levels increasing from 20 mg/day up to the maximum administered dose (Part A) followed by cohort expansion at the recommended dose (RD; Part B). The study will also assess two dose levels of SAR439859, in combination with palbociclib 125 mg/day (Days 1–21 in 28-day cycles; Part C) followed by cohort expansion (Part D). Postmenopausal women with ER+/HER2- metastatic breast cancer, who received ≥ 6 months of prior endocrine therapy, are eligible. Patients were permitted to have received ≤ 3 (Part A) or ≤ 1 (Parts B–D) prior chemotherapies for metastatic disease. Exclusion criteria include Eastern Cooperative Oncology Group performance status ≥ 2, concomitant illness (including those related to HIV or hepatitis and other cancers ≤ 3 years) and factors potentially affecting absorption of SAR439859 or palbociclib. Study endpoints include assessment of dose-limiting toxicities, determination of maximum tolerated dose and RD in dose escalation (Parts A and C), and objective response rate according to RECIST v1.1 in dose expansion (Parts B and D). 18 FES-PET scan between Days 11–15 in Part A will assess ER availability. Safety, pharmacokinetics and response were evaluated for Parts A–D. Recruitment and screening are ongoing (Part A n = 16; B n = 18; C n = 2; D n = 0). Funding: Sanofi. Clinical trial information: NCT03284957.
Reassignment of HER2 status for subgroups of breast cancer according to the 2018 updated American Society of Clinical Oncology and College of American Pathologists guidelines: The impact of combined immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) reflex testing in a large national reference laboratory.
Authors: Katherine Geiersbach, Reid G. Meyer, Sara M. Kloft-Nelson, Darlene L. Knutson, Ryan A. Knudson, William R. Sukov, Rhett P. Ketterling, Patricia T. Greipp, Robert B. Jenkins
Journal: Journal of Clinical Oncology (2019)

3144 Background: Updated ASCO/CAP Guidelines for HER2 testing in breast cancer have been most impactful on the resolution of certain challenging groups of FISH results. We review the change in assignment of HER2 status in a large series of breast cancers referred to a large national reference laboratory for FISH testing since the introduction of the 2018 updated guidelines. Methods: Patient samples submitted to the Mayo Clinic Cytogenetics Laboratory (N = 2208) were analyzed by FISH. Samples with Group 2, Group 3, or Group 4 FISH results were reflexed to immunohistochemistry (IHC) in our central laboratory; FISH slides for those cases with equivocal 2+ IHC results were re-scored in the regions of invasive cancer showing more intense membranous staining. A subset of 202 samples with Group 4 FISH results were also reflexed to the previously employed reflex FISH assay (HER2/D17S122), and these were also re-analyzed according to the new reflex IHC/FISH process. Results: 382 of 2208 breast cancer samples tested (17.3%) had FISH results categorized as Group 2 (N = 17, 0.8%), Group 3 (N = 34, 1.5%), or Group 4 (N = 331, 15%) and required reflex IHC testing, and of those, 75% were 2+ equivocal and required targeted re-analysis of the FISH slide according to the 2018 updated guidelines. Re-analysis of the FISH slide resulted in switching between Groups 1-5 in 19.4% of cases, but HER2 status was changed by FISH re-scoring in only 7.7% of cases re-scored (1.0% of all samples), generally due to only minor shifts in HER2 copy number and HER2/control ratios between the initial and IHC-guided reflex FISH scores. In the subset of 202 cases tested by both reflex methods, the previously employed HER2/D17S122 reflex probe set was positive in 123 cases (60.9%), whereas reflex IHC/FISH was positive in only 10 cases (7.9%). Including positive reflex IHC (0.4%) and positive reflex FISH results (2.1%), the overall assignment of positive HER2 status on our series of 2208 cases was 11.5%. Conclusions: Overall rates of HER2 positive FISH results have declined under the most recent ASCO/CAP guideline update as a consequence of new recommendations for reflex testing for Groups 2-4. This change is largely due to reassignment of Group 2 and Group 4 results as negative in the absence of positive IHC.