tbuckley/cabot-search huggingface dataset:
Phase I study of the Aurora A kinase (AurA) inhibitor TAS-119 with paclitaxel (P) in advanced solid tumors.
Authors: Dana Backlund Cardin, Haeseong Park, Jennifer Robinson Diamond, Alexander E. Drilon, Wendy L. VerMeulen, Xiaomin He, Hiroshi Hirai, Nital Soni, Jordan Berlin
Journal: Journal of Clinical Oncology (2019)

3031 Background: AurA is a key regulator of cell division, including mitotic spindle assembly. However, elevated levels of AurA have been reported to abrogate the mitotic spindle checkpoint activated by taxanes leading to treatment resistance. Preclinical studies of TAS-119 + P showed enhanced antitumor activity and suggested an optimal timing window of the combination. Study objective was to assess the safety of TAS-119 + P in adult patients (pts) with advanced solid tumors. Methods: Dose escalation used a 3+3 design to determine the maximum tolerated dose (MTD); 7 dose levels (DLs) were explored, starting with 25 mg TAS-119 BID dosed 4 days/week (d/wk) and weekly 90 mg/m 2 P for 3 weeks of a 4 week cycle (DL1). Plasma samples were collected during cycle 1 to evaluate pharmacokinetics. In expansion, pts with advanced breast/ovarian cancers were treated at the MTD. Results: Dose escalation enrolled 26 pts with various cancers, the majority being pancreas, colon, and ovarian; 2 pts were not evaluable for DLT assessment and replaced. A DLT (neutropenia and elevated AST) was observed in 2/3 pts in DL1. Dosing was modified to 25 mg TAS-119 BID 2 d/wk and P 70 mg/m 2 (DL2) and no DLTs were observed. Zero DLTs were observed in the next 4 doses: 70 mg/m 2 P + TAS-119 2 d/wk at 50 mg BID (DL3) or 75 mg BID (DL4), or 80 mg/m 2 P + TAS-119 at 75 mg BID 2 d/wk (DL5) or 75 mg BID 3 d/wk (DL6). TAS-119 was escalated to 100 mg BID 3 d/wk (DL7) and 3 DLTs (n=1, elevated ALT; n=1, diarrhea and mucositis) occurred in 2/3 pts. Three additional pts were then enrolled at DL6 to confirm the MTD. One breast and 2 ovarian pts were enrolled in expansion before the trial was suspended by the company. Toxicities observed in ≥30% of pts were diarrhea, nausea, and fatigue (most ≤Gr2). Plasma TAS-119 exposure increased dose-proportionally in 2 d/wk and 3 d/wk schedules; no impact of TAS-119 on PK of paclitaxel was found. The disease control rate was 59% (17/29); 4 of these pts had a partial response. Conclusions: The combination had a manageable toxicity profile at the MTD of 80 mg/m 2 P + TAS-119 at 75 mg BID 3 d/wk. Preliminary clinical activity was seen in 59% of pts, including tumor responses in a majority (4/7) of pts with ovarian/fallopian tube cancers. Clinical trial information: NCT02134067.
Can the enumeration of circulating tumor cells (CTCs) and the characterization of circulating tumor DNA (ctDNA) provide insight into organ tropism in metastatic breast cancer (MBC)?
Authors: Lorenzo Gerratana, Qiang Zhang, Ami N. Shah, Andrew A. Davis, Youbin Zhang, Firas Wehbe, Wenan Qiang, Lisa E. Flaum, Brian Finkelman, William John Gradishar, Leonidas C. Platanias, Amir Behdad, Massimo Cristofanilli
Journal: Journal of Clinical Oncology (2019)

3038 Background: Liquid biopsy provides real-time data about prognosis and actionable mutations in MBC. The aim of this study was to explore the combination of ctDNA analysis and CTCs enumeration in estimating target organs more susceptible to MBC involvement. Methods: This retrospective study analyzed 85 MBC patients (pts) characterized for both CTCs and ctDNA at baseline. CTCs were isolated through the CellSearch kit (Menarini Silicon Biosystems, PA), while ctDNA was analyzed using the Guardant360 NGS-based assay (Guardant Health, CA). Pts with ≥ 5 CTC/7.5 ml of blood were defined as Stage IV aggressive as previously reported (Cristofanilli et al 2019). Statistical associations were explored through uni- and multivariate logistic regression and Fisher’s exact test. Results: 37% of pts were diagnosed with hormone receptor positive (HRpos) MBC, 26% with HER2-positive MBC and 37% with triple negative MBC (TNBC), 28 pts (33%) were defined as stage IV aggressive. The most observed metastatic sites were bone (37%), lymph nodes (29%), lung (27%) and liver (25%). In multivariate analysis, IBC and ESR1 mutations were the only significant factors associated with liver metastases (respectively, OR 0.12, P = 0.038 and OR 24.01, P = 0.019), while no associations were found with respect to lung localizations. Intriguingly, all HRpos MBC pts with ESR1 mutations had bone metastases (P = 0.022), while IBC and Stage IV aggressive were independently associated with bone metastases (respectively OR 0.10, P = 0.006 and OR 19.92, P = 0.003). FGFR1 and NF1 were associated with lymph node localizations (OR 3.68, P = 0.046, OR 4.39, P = 0.031, respectively), while CDK6 and TP53 alterations were associated with serosal involvement (OR 14.34, P = 0.029, OR 0.08, P = 0.031, respectively). Notably, TNBC and IBC were both associated with soft tissue spreading (respectively OR 3.7, P = 0.011, OR 2.79, P = 0.018). Conclusions: These results suggest that ctDNA and CTCs enumeration could give useful insights on MBC organotropism, suggesting a possible role for future monitoring strategies that dynamically focus on high-risk organs defined by tumor biology.
Association between time to first subsequent therapy (TFST) and overall survival (OS) in previously untreated patients with ovarian cancer (OC): A SEER Medicare database analysis.
Authors: Kaushal Desai, Dominic Muston, Gboyega Adeboyeje, Matthew J. Monberg
Journal: Journal of Clinical Oncology (2019)

e17095 Background: TFST may be a patient-relevant indicator of efficacy beyond progression in OC, however, the association between TFST and OS is unknown. We analyzed the SEER Medicare database to determine whether OS varied by TFST in previously untreated patients with OC. Methods: From the SEER-Medicare linked database, we identified newly diagnosed OC patients (≥66 years) who initiated first-line chemotherapy between 2009 and 2015. Patients were followed through the end of 2016. TFST was defined as the time from initiation of first-line chemotherapy until the start of subsequent therapy or death. Cox models summarized the overall association between TFST and OS through hazard ratios (HRs), and by TFST strata for patients who had a TFST event. In case hazards were non-proportional, we examined the fit of independent parametric survival curves. Results: In the cohort of 1407 patients, 1005 patients had a TFST event. Median age was 74 years and 34.9% were alive at the time of this analysis. For population with a TFST, the median TFST was 13.1 months and median OS was 30.88 months (HR = 0.29, 95% CI: 0.26, 0.32). Among patients &lt; 75 years, the median TFST was 13.65 months and the median OS was 37.07 months (HR = 0.24, 95% CI: 0.21, 0.28). In the full cohort of 1407 patients, the best-fitting distributions accelerated failure time models under which the (unrestricted) mean TFST and OS were 44.9 and 73.8 months respectively. This indicated that on average TFST was an acceleration of OS by a factor of 39%. Conclusions: In this elderly population of previously untreated OC, longer TFST was associated with longer OS. Limitations of this analysis include censoring of OS and immortal time bias. [Table: see text]
Real-world evidence evaluating the use of an NK-1 antiemetic in the systemic chemotherapy treatment of metastatic breast cancer.
Authors: Kevin Lord, Bruce A. Feinberg, Jonathan Kish, Jalyna R. Laney, Dhruv Chopra, Djibril Liassou
Journal: Journal of Clinical Oncology (2019)

e12599 Background: Severe and persistent nausea and vomiting (n/v) impacts quality of life and may lead to treatment discontinuation. While antiemetics assist with minimizing these effects, newer drugs can be expensive and carry their own side effect profile. Prior research has suggested that neurokinin 1 receptor inhibitor(NK-1) antiemetics are overly prescribed. Using the package insert recommendations for aprepitant, an NK-1, we evaluated the frequency of its prophylactic use to prevent emesis in patients receiving systemic chemotherapy(chemo) with moderate to high emetogenic risk. Methods: Patients were identified from a third-party, administrative claims database. Using medical and pharmacy claims, any female with ICD-9/10 codes for both breast cancer and metastases diagnosed between Jan-2013 and Dec-2017, who initiated systemic chemo and received aprepitant prophylactically were selected. Chemo regimen emetogenic potential was scored using the Hesketh scale and aggregated into two cohorts: low risk (grade 1-2 = none- &lt; 30%), and moderate-high risk (grade 3-5: &gt; 30- &gt; 60%). If patients received combination chemo, the assigned risk level was the highest risk of any individual agent. The frequency of NK-1 use for each risk cohort was calculated per line of therapy independent of the previous treatment. Results: 10,342 patients met the selection criteria with 2,868 patients administered moderate-high emetogenic risk chemotherapy regimens. Mean age at initiation of treatment was 61.7 years (SD = 12.12). By line, the aprepitant utilization rate was: 1 line(L) 43% ,2L 27%, 3L 18%, 4L 16%, 5L 11% and 6L 12%. Across all lines of therapy, aprepitant was used prophylactically in 23% of patients treated with high risk chemo regimens and in 2% of patients who had received low risk regimens. Conclusions: Prophylactic use of the NK-1 inhibitor aprepitant was less than 50% in 1L moderate-high emetogenic risk chemotherapy and declined with consecutive lines of treatment. NK-1 use with low risk regimens was minimal. Further research is needed to understand the pattern of use and clinical outcomes between moderate-high emetogenic risk patients who do and don't receive NK-1 antiemetic supportive care.
Advance care planning and terminal intensive care unit admissions for cancer patients: We can do better.
Authors: Joseph Heng, Ramy Sedhom, Thomas J. Smith
Journal: Journal of Clinical Oncology (2019)

e23000 Background: Terminal oncology intensive care unit (ICU) admissions are associated with high healthcare costs and decreased quality of life. Chemotherapy can be given in non-curative settings to optimize symptom control, but use of it at the end of life does not improve longevity. In addition, goals of care are too often not addressed for patients at high risk of death. Methods: We carried out a retrospective review identifying patients of a large academic cancer center who were admitted to and expired in an ICU between January 1, 2017 to December 31, 2018. Results: 120 patients met inclusion criteria. Median age was 58 years. Only 15.0% (n = 18) of all patients had advance directives. The majority of patients (94.1%, n = 113) were FULL CODE on admission. Median duration of admission was 10 days. Median time to death from ICU admission was 7.5 days. 65.0% (n = 78) of all patients were intubated, while 15.0% (n = 15) received CPR. 58.3% (n = 70) of the study population had solid malignancies; of note, 97.1% (n = 68) of these patients were metastatic at presentation and had a median ECOG performance status of 2. Patients with metastatic solid tumors typically have a more indolent course of progression compared to patients with hematologic malignancies. However, only 23.5% (n = 16) had discussed goals of care or code status with their outpatient oncologists, despite many seeing them within the last month prior to admission (83.8%, n = 57). Similarly, only 4.0% (n = 2) of patients with hematologic malignancies had advance care planning discussions with their oncologists prior to their terminal ICU admission. 27.5% (n = 33) of all patients had an inpatient palliative care consult. The inpatient pulmonary/critical care team had a high rate of inpatient code status transitions, with 85.6% (n = 97) of FULL CODE admissions transitioning to DNR/DNI. Conclusions: These findings reflect contemporary practice at a major academic cancer center. Despite most patients having regular contact with their outpatient oncologists, the intensity of health care utilization noted highlights a need to optimize recognition of patients at high risk of death and to engage patients in advance care planning discussions to avoid terminal ICU admissions.
Case 37-1986
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, Betty U. McNeely, J.H. Maguire, A.E. Rosenberg
Journal: New England Journal of Medicine (1986)

Presentation of CaseA 50-year-old woman was admitted to the hospital because of an osteolytic lesion of the spine.She was well until six months earlier, when she experienced the abrupt onset of low-back pain that radiated down the left leg, accompanied by migratory arthralgia involving the ankles, wrists, elbows, shoulders, and right temporomandibular joint; the right elbow and left ankle became swollen. The joint pains subsided after two months, but back pain persisted, shifted to the low dorsal region, and was aggravated by walking. An extensive work-up performed elsewhere revealed that the urine was normal. The hematocrit was 37 . . .
Pembrolizumab (Pem) for advanced non-small cell lung cancer (aNSCLC): Efficacy and safety in everyday clinical practice.
Authors: Doran Ksienski, Elaine S. Wai, Nicole Croteau, Ashley Freeman, Leathia Fiorino, Angela Chan, Georgia Samantha Geller, Zia Poonja, Edward Geoffrey Brooks, Dave Fenton, Sarah Irons, Mary Lesperance
Journal: Journal of Clinical Oncology (2019)

e20506 Background: In clinical trials, Pem improves overall survival (OS) compared to chemotherapy in a subset of patients (pts) with aNSCLC. Immune related adverse events (irAE) have correlated with improved OS in some studies. We explored efficacy and safety of Pem in a provincial population. Methods: aNSCLC pts treated with Pem between 06/2015 and 08/2018 at BC Cancer were retrospectively identified. Kaplan-Meier curves of OS from initiation of Pem were plotted and multivariable analysis (MVA) was performed with Cox proportional hazard regression models. 3, 6, and 9 month landmark Kaplan-Meier analysis was performed and log-rank tests used to determine the association of irAE subtypes with OS. Multivariable logistic regression models for irAE within 3 months of Pem initiation were also fit. Results: Characteristics of the 190 pt cohort: median age 70y (41-91), ECOG PS 2/3 at start of Pem: 34.2%, squamous histology: 22.1%, EGFR mutation: 3.7%, brain (13.7%) or liver (8.9%) metastases, PD-L1 expression ≥ 50%: 92.6%, treatment line: 1 st / ≥2 nd : 74.2%/25.8%. Median cycles delivered 7 (range 1-35). With median survival follow-up of 6.1 months (range 0.03-39.8 months) and 43% pts decreased, median OS of Pem in the 1 st line and ≥2 nd line settings were 24.3 months (95% CI, 9.7-not reached, NR) and 13.4 months (95% CI, 8.1-NR), respectively. Pts with ECOG PS 2/3 had lower OS vs. ECOG PS 0/1 (5.8 months vs. 16.7 months, log-rank p &lt; 0.0001). On MVA, only ECOG PS (p &lt; 0.001) was associated with OS. 66 pts (34.7% of cohort) experienced 89 irAE; most common irAE: dermatitis (20pts), hypothyroidism (13pts), and pneumonitis (10pts). 8.4% of cohort developed grade 3 or 4 irAE; no grade 5 irAE. The odds of a grade ≥ 3 irAE within 3 months was 6.3 fold higher if ECOG 2/3 vs. 0/1 (p = 0.05). A weak association between pneumonitis and decreased OS at 9 month landmark (p = 0.09) was seen; otherwise no association with irAE subtypes at 3, 6, and 9 month landmarks was observed. Conclusions: In the whole cohort, clinical efficacy and toxicity of Pem was consistent with registration trials. Pts with ECOG PS 2/3 had a significantly lower OS and higher odds of developing grade ≥ 3 irAE than those with good ECOG PS 0/1.
A phase II randomized trial for early-stage squamous cell carcinoma of the oropharynx: Radiotherapy versus trans-oral robotic surgery (ORATOR).
Authors: Anthony Charles Nichols, Julie Theurer, Eitan Prisman, Nancy E Read, Eric Berthelet, Eric Tran, Fung Kevin, John R. de Almeida, Andrew Hope, David Paul Goldstein, Michael Hier, Khalil Sultanem, John Yoo, S. Danielle Macneil, Eric Winquist, Alex Hammond, Varagur Venkatesan, Sara Kuruvilla, Libni Eapen, David A. Palma
Journal: Journal of Clinical Oncology (2019)

6006 Background: The incidence of OPSCC has risen rapidly, due to an epidemic of human papillomavirus (HPV) infection. Radiation therapy (RT) has historically been the standard treatment, but transoral robotic surgery (TORS) has surpassed RT in the US as the most common approach, based on assumptions of reduced toxicity or improved quality of life (QOL). No randomized trials have previously compared these treatments. Methods: The ORATOR trial (NCT01590355) enrolled patients with T1-T2 N0-2(≤4 cm) OPSCC amenable to TORS. We randomly assigned patients, stratified by p16 status, to RT (70 Gy/35 fractions, with chemotherapy if N1-2) vs. TORS (± adjuvant [chemo]RT based on pathology). The primary endpoint was a definitive comparison of swallowing QOL at 1-year using the MD Anderson Dysphagia Inventory (MDADI), powered to detect a 10-point improvement (a clinically-meaningful change [CMC]) in the TORS arm. Secondary endpoints included adverse events (AEs), other QOL outcomes [including EORTC scales, the Voice Handicap Index-10, Neck Dissection Impairment Index, and Patient Neurotoxicity Questionnaire], overall- and progression-free survival (OS, PFS). All analyses were pre-specified and intention-to-treat. Results: Between 2012 and 2017, 68 patients were randomized (n = 34 in each arm), in Canada and Australia. Median age was 59 years; 87% were male. Primary tumor sites were palatine tonsil (74%) or base of tongue (26%). Arms were well-balanced for baseline factors, including p16 status (88% in each arm). Median follow-up was 27 months. MDADI scores at 1-year were statistically superior in the RT arm (mean ± SD: 86.9 ± 11.4 vs. 80.1 ± 13.0 in the TORS arm; p = 0.042), but not meeting the definition of a CMC. For the other QOL metrics, outcomes were similar at 1-year. Feeding tube rates at 1-year were 3% (n = 1) vs. 0% respectively. Rates of treatment-related grade ≥2 AEs were similar (91% vs. 100%, p = 0.24), with more neutropenia, constipation and tinnitus in the RT arm and more trismus in the TORS arm (all p &lt; 0.05). There was one TORS bleeding-related death. OS and PFS were similar. Conclusions: RT had superior swallowing QOL scores at 1 year compared to TORS, but the difference was not a CMC. Toxicities differed between the arms. This study provides the first level 1 evidence to inform patients of the QOL impact of both approaches. Clinical trial information: NCT01590355.
Association between nutritional status (NS) and health-related quality of life (HRQoL) in men with early metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Luka Cavka, Maja Pohar Perme, Nada Rotovnik Kozjek, Bostjan Seruga
Journal: Journal of Clinical Oncology (2019)

e16539 Background: HRQoL is of paramount importance in men with mCRPC. It is not known how NS affects HRQoL in this population of patients. We hypothesized that NS is associated with HRQoL in men with early mCRPC and that NS outperforms body mass index (BMI) in this association. Methods: We prospectively enrolled men with early mCRPC into this study. Patients were assessed, and on the basis of established criteria, four NS categories were defined: normal NS (nNS), nutritional risk without cachexia/sarcopenia (NR), sarcopenia (S) (handgrip strength &lt; 30 kg) and cachexia (C) (Evans`s criteria). HRQoL was assessed by the validated questionnaire Functional Assessment of Cancer Treatment (FACT-P); higher score reflects better HRQoL. After checking for normal distribution, we performed a linear regression model for HRQoL with NS as a dummy variable (with nNS as the reference group). Age, duration of previous androgen deprivation therapy (ADT), hemoglobin level (Hb), prostate-specific antigen (PSA) and BMI were included as covariates into the multivariate model. Results: One hundred forty-one patients were enrolled in our study. At presentation, their mean age was 74.2 years (SD 7.1), and 18 (12.4 %) had visceral metastases. Fifty-eight (41.3%) had nNS, 43 (30.8 %) had sarcopenia, 24 (16.8 %) NR and 16 (11.2 %) C. Mean FACT-P score [SD] in nNS was 115.3 points [22.2], following by 97 [24.6], 98.3 [22.4] and 78.8 [25] points in NR, S and C groups, respectively. We found a significant and consistent association between better NS and worse HRQoL (β [NR:nNS] = -18.2 points; β [S:nNS] = -17 points; β [C:nNS] = -36.5 points; p &lt; 0.001; R² = 0.2). The association remained significant after adjustments (R² = 0.27). Conclusions: Suboptimal NS but not BMI is significantly associated with worse HRQoL in men with early mCRPC. Interventional trials focused on the optimization of NS in men with mCRPC are warranted.[Table: see text]
Ki67 during and after neoadjuvant trastuzumab, pertuzumab and palbociclib plus or minus fulvestrant in HER2 and ER-positive breast cancer: The NA-PHER2 Michelangelo study.
Authors: Luca Gianni, Marco Colleoni, Giancarlo Bisagni, Mauro Mansutti, Claudio Zamagni, Lucia Del Mastro, Stefania Zambelli, Antonio Frassoldati, Simona Barlera, Pinuccia Valagussa, Giuseppe Viale
Journal: Journal of Clinical Oncology (2019)

527 Background: Downregulation of Ki67 by neoadjuvant endocrine therapy predicts activity of endocrine treatments in hormone receptors positive breast cancer. NA-PHER2 is an exploratory phase II study (NCT02530424) assessing Ki67 changes in patients with HER2+ and ER+ breast cancer undergoing dual HER2 block and palbociclib. Cohort A of the NA-PHER2 showed significant decrease of Ki67 at week 2 and at surgery and pathological complete response (pCR) in 27% of patients (Lancet Oncol 2018). Methods: After completing cohort A two additional cohorts were started. In Cohort B cases with HER2 3+ or amplified unilateral breast cancer received therapy with dual block and palbociclib without fulvestrant. In Cohort C tumors with Ki67 &gt;20% and HER2 low (1+/2+, no amplification) received also fulvestrant. Trastuzumab and pertuzumab q3 wks were dosed for 6 cycles and palbociclib for 5 cycles (125 mg po q.d. 3q4 wks). Fulvestrant in Cohort C was given im 500 mg q4 wks for 5 cycles. Primary endpoint was Ki67 change from baseline to 2 weeks and at surgery. Results: 26 eligible patients in cohort B and 23 in cohort C with centrally confirmed HER2 and ER status were recruited. Ki67 was centrally assessed. Main results are reported in the table. Clinical trial information: NCT02530424. The most frequent G &gt;=3 adverse events were neutropenia (36%) and gastrointestinal disorders (12%). Conclusions: Dual block of HER2 and palbociclib caused robust persistent decrease of Ki67 as in cohort A. In cohort B without endocrine therapy there also were pCR and high objective response rate. Effects on Ki67 and ORR were similar in HER2 low tumors. The chemo-free approach of NA-PHER2 leads to promising therapeutic effects and deserves investigation in ER+ HER2+ tumors to spare the toxicity of chemotherapy, and in HER2-low tumors, in which functional activation of HER2 may lead to resistance to endocrine therapy. Supported in part by unrestricted grants of Pfizer Italia S.r.l. and Roche S.p.a. Italia.[Table: see text]