tbuckley/cabot-search huggingface dataset:
The maturation stage of tumoral tertiary lymphoid structures to predict recurrence risk in localized colorectal cancer.
Authors: Florian Posch, Karina Silina, Ulf Petrausch, Sebastian Leibl, Axel Muendlein, Holger Moch, Alexander Rheinhard Siebenhuener, Bernhard C. Pestalozzi, Jakob M. Riedl, Michael Stotz, Joanna Szkandera, Herbert Stoger, Martin Pichler, Roger Stupp, Peter Schraml, Armin Gerger, Thomas Winder
Journal: Journal of Clinical Oncology (2017)

e15083 Background: The tumor immune infiltrate and organized lymphocytic aggregates within the tumor microenvironment, known as tertiary lymphoid structures (TLS), play a critical role in cancer. We hypothesize that the maturation stage of TLS harbors prognostic information on recurrence risk in patients (pts) with non-metastatic colorectal cancer (nmCRC). Methods: In a comprehensive immunofluorescence and clinical analysis of 111 pts with UICC stage II &amp; III nmCRC (median age: 65 yrs; female: n = 53 (48%); stage III: n = 69 (62%)), we quantified the number and maturation status of tumor-associated TLS in baseline surgical specimens:[1] Early TLS (E-TLS, composed of dense lymphocytic aggregates without follicular dendritic cells (FDCs), [2] Primary follicle-like TLS (PFL-TLS, having FDCs but no germinal center (GC) reaction), and [3] Secondary follicle-like TLS (SFL-TLS, having an active GC reaction). The 3-year incidence of recurrence was the primary endpoint of this study, which occurred in 19 pts (3-year recurrence risk = 18.3%). Results: Most TLS formed in tissue adjacent to the tumor. The median number of TLS/mm of tumor perimeter was 1.0 [25 th -75 th percentile: 0.5-1.7]. The average proportions of different TLS maturation stages were 56% of E-TLS [40-78], 20% of PFL-TLS [6-37], and 16% of SFL-TLS [0-32]. A structural equation model was fitted to summarize the TLS counts and maturation stages into a TLS maturation immunoscore for predicting recurrence. 3-year recurrence risks were 31.7% (95%CI: 17.2-47.3), 15.9% (5.7-30.5), and 9.4% (2.4-22.4) in pts in the 1 st , 2 nd , and 3 rd tertile of the score (Gray’s test p = 0.05). A higher score was significantly associated with a lower recurrence risk (Hazard ratio (HR) for 10 units increase = 0.76, 95%CI: 0.59-0.97, p = 0.03), and this association prevailed in multivariable analysis adjusting for age, ECOG performance status, stage, and adjuvant chemotherapy (Adjusted HR = 0.73, 0.54-0.99, p = 0.05). Conclusions: Tumors of nmCRC pts with a very low risk of recurrence are characterized by an increased fraction of mature TLS comprising FDCs and GCs. If confirmed prospectively, adjuvant chemotherapy may be avoided in nmCRC pts with a high TLS maturation score.
A phase I study of bevacizumab in combination with niraparib in patients with platinum-sensitive epithelial ovarian cancer: The ENGOT-OV24/AVANOVA1 trial.
Authors: Mansoor Raza Mirza, Christiane Ehlers Mortensen, Rene dePont Christensen, Louise Christoffersen, Mia Westergaard, Louisa Boufercha, Michael Birrer, Elisabeth Avall-Lundqvist, Line Bjorge, Johanna Unelma Maenpaa
Journal: Journal of Clinical Oncology (2016)

5555 Background: PARP-inhibitors and anti-angiogenic agents are active substances against ovarian cancer (OC). We investigated the safety, tolerability and Recommended Phase 2 Dose (RP2D) of the combination of niraparib, a PARP-inhibitor, and bevacizumab. NCT02354131 Methods: This single-arm study enrolled patients with platinum-sensitive high-grade serous/endometrioid OC. Any number of previous chemotherapy courses was permitted. In 3+3 design the patients received fixed dose bevacizumab (15mg/kg iv q 21 days) with dose escalation of niraparib (100, 200, 300mg oral, daily). Prior anti-angiogenic therapy was permitted. The primary objectives were to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of the bevacizumab-niraparib combination therapy and to decide the RP2D of this combination. Results: 12 patients (3+3+6) were enrolled to three dose levels. 3 patients had gBRCA2 mutation, while others were gBRCAwt. Common related toxicities at cycle 1 were hypertension (G3 = 5), anaemia (G3 = 3), thrombocytopenia (G3 = 1), fatigue (G2 = 1), constipation (G2 = 1), and nausea (G2 = 1). One DLT (Grade 3 thrombocytopenia that persisted for ≥ 5 days) was observed at the highest dose level (bevacizumab 15 mg/kg iv q 21 days; niraparib 300mg daily). The RP2D is bevacizumab 15 mg/kg iv q 21 days with niraparib 300mg daily. Niraparib dose reductions were needed in 4 pts (cohort 2 = 1; cohort 3 = 3), bevacizumab dose interruptions in 2 pts. First patient entered study on April 20, 2015. Median number of cycles delivered to date is 48. Ten patients are continuing treatment while 2 pts have ended treatment (1PD; 1 withdrawal of consent). Disease control rate is 91%, response rate 45% (1CR, 4PR). Conclusions: Bevacizumab-niraparib combination has hematologic DLT and manageable class toxicities. This combination has preliminary evidence of efficacy. A phase 2 randomized trial is on-going (AVANOVA2). Clinical trial information: NCT02354131.
Documenting goals of care (GOC) and prognosis of patients with advanced cancer: A tertiary cancer centre review of internal and external correspondence.
Authors: Anis Hamid, Francis Ha, Oindrila Das, Andrew Weickhardt
Journal: Journal of Clinical Oncology (2017)

e21512 Background: Patients with advanced cancer require clear communication and documentation of GOC and prognosis to inform optimal care planning between the patient, family, specialist and primary healthcare providers. Such documentation may be lacking despite multiple inpatient and outpatient (OP) interactions prior to death. We aimed to review the frequency, content and timing of GOC/prognosis documentation during the last year of life of advanced cancer patients. Methods: All patients who died during palliative care admission at our tertiary centre in 2015 were identified. Patients with incurable solid cancer and reviewed ≥1 times in oncology OP clinic were included. We reviewed all oncology OP consultation notes and letters, oncology discharge summaries and advanced care plans (ACP) over a 12 month period before death. Both internal (OP notes) and external documents (OP letters; discharge summaries) were reviewed in detail for documentation of GOC and prognosis (qualitative/quantitative description). Results: 147 patients were included in the analysis. There was a median of 6 OP consultations and 6 hospital encounters (including admissions) per patient. Median time from first OP consultation to death was 7.7 months. Most patients had documentation of GOC in OP notes (61%) however only 24% had prognosis documented. 63% of OP visits resulted in a letter to external doctors. 58% of patients had ≥1 OP letter documenting GOC (median time before death, 3.9 months) and 16% had a letter documenting prognosis (median time before death, 2.8 months). 73% of patients had a ward admission yet 5% of discharge summaries specified prognosis. Only 15% of patients had an accessible ACP on record. Conclusions: We observed a lack of documentation of GOC and particularly prognosis in internal and external hospital correspondence despite multiple interactions prior to patient death. Although discussion of GOC and prognosis may occur within a consultation, lack of documentation in correspondence reduces insight into patient clinical trajectory and may result in differing care between providers. There is a need for improved communication and documentation in advanced cancer care.
Measuring the effect of adjuvant chemotherapy on function-related adverse outcomes among older breast cancer patients.
Authors: Caroline Joy Mariano, Jennifer Leigh Lund, Sharon Peacock Hinton, Phyto Htoo, Katherine Elizabeth Reeder-Hayes
Journal: Journal of Clinical Oncology (2016)

10052 Background: The incidence of specific complications of adjuvant chemotherapy in breast cancer is well documented in clinical trials. However, the effect of chemotherapy on functional outcomes in older patients (pts) is unknown. We identified a large cohort of older, early stage breast cancer pts to examine the effect of exposure to cytotoxic chemotherapy on a claims-based measure of function-related adverse outcomes (FAE) Methods: Using the SEER-Medicare data, we identified women aged ≥66 diagnosed with stage I or II breast cancer from 2004-2011. Exposure to chemotherapy was defined as receipt of ≥1 dose of cytotoxic therapy within 90 days of surgery. FAE was defined as at least one claim suggestive of functional impairment within 24 months post-exposure, including claims for durable medical equipment (DME) (wheelchair, walker, cane, hospital bed, home oxygen, bath/toilet equipment) and skilled nursing (home visits and skilled nursing facility use). Women who did not receive chemotherapy were weighted to reflect the covariate distribution of those who received chemotherapy using propensity score (PS) weighing adjusting for age, stage, healthcare utilization, and comorbidities. Results: Of 44626 pts, 6892 (15%) received chemotherapy. Age distribution: 52% 66-74, 39% 75-84, 9% 85+. Chemotherapy was more common in younger pts and those with positive nodes and grade 3 tumors. After PS weighting, chemotherapy was associated with a small increased risk of FAEs (weighted hazard ratio (HR)=1.11, Table 1). Conclusions: Exposure to chemotherapy was associated with a small risk of function-related adverse outcomes. This data should be used to inform decision making for older breast cancer patients being considered for adjuvant chemotherapy. Incidence of FAE by chemotherapy exposure. No Chemo group Chemo group Unadjusted HR Adjusted HR Events Crude incidence /1000 person years Events Crude incidence/ 1000 person years Any FAE 7484 114.6 1211 101.7 0.89 (0.84, 0.94) 1.11 (1.04, 1.20) DME claims 4497 65.7 770 61.9 0.94 (0.87, 1.02) 1.14 (1.05, 1.25) Skilled care claims 5916 88.4 924 75.4 0.85 (0.80, 0.92) 1.12 (1.04, 1.22)
4-year overall survival for patients with advanced NSCLC treated with pembrolizumab: Results from KEYNOTE-001.
Authors: Enriqueta Felip, Matthew David Hellmann, Rina Hui, Enric Carcereny, Natasha B. Leighl, Myung-Ju Ahn, Joseph Paul Eder, Ani Sarkis Balmanoukian, Charu Aggarwal, Leora Horn, Amita Patnaik, Matthew A. Gubens, Suresh S. Ramalingam, Erin Jensen, Debra A. Kush, Edward B. Garon
Journal: Journal of Clinical Oncology (2018)

9030 Background: Pembrolizumab (pembro) has shown antitumor activity in patients (pts) with advanced NSCLC and is standard-of-care therapy for pts with PD-L1‒expressing tumors (first-line, TPS ≥50%; previously treated, TPS ≥1%). KEYNOTE-001, an open-label phase 1b study, evaluated pembro monotherapy in treatment-naive or previously treated pts with advanced NSCLC (NCT01295827). We report a 4-y update of KEYNOTE-001. Methods: Pts had confirmed locally advanced/metastatic NSCLC and provided a contemporaneous tumor tissue sample for evaluation of PD-L1 levels by IHC using the 22C3 antibody. Pts received pembro 2 mg/kg Q3W or 10 mg/kg Q2W or Q3W. Primary efficacy endpoint was ORR. OS was a secondary endpoint. Results: As of data cutoff (Sep 1, 2017), among 550 pts enrolled (treatment-naive, n = 101; previously treated, n = 449), median (range) follow-up was 46.5 (37.7–63.8) mo. ORR (by investigator per irRC) was 41.6 % (95% CI, 31.9–51.8) for treatment-naive pts and 22.9% (95% CI, 19.1–27.1) for previously treated pts. Median OS was 22.3 mo (95% CI, 17.1–32.3) for treatment-naive pts and 10.5 mo (95% CI, 8.6–13.2) for previously treated pts; estimated 4-y OS rates were 27.2% and 16.4 %, respectively. Kaplan-Meier curves for OS appeared to plateau after 42 mo for treatment-naive pts and 36 mo for previously treated pts. Increased PD-L1 expression was associated with improved OS (Table). Immune-mediated AEs occurred in 24.8% of treatment-naive and 17.4% of previously treated pts. No additional grade 5 treatment-related AEs occurred (compared with 3-y follow-up; data cutoff Sep 1, 2016). Conclusions: Pembro provides long-term OS benefit for both treatment-naive and previously treated advanced NSCLC that expresses PD-L1. These data represent the longest efficacy and safety follow-up for pts with advanced NSCLC treated with pembro. Clinical trial information: NCT01295827.OS in subgroups defined by PD-L1 TPS. Treatment-Naive (N = 101) Previously Treated (N = 449) n Median (95% CI), mo Est. 4-y rate n Median (95% CI), mo Est. 4-y rate TPS ≥50% 27 35.4 (20.3‒NE) 48.1% 138 15.4 (10.6‒18.8) 24.8% TPS 1%–49% 52 19.5 (10.7‒26.3) NE 168 8.5 (6.0‒12.6) 15.6% TPS ≤1% Not reported* 90 8.6 (5.5‒10.6) 6.5% NE = not estimable. *Due to small pt numbers (n = 12).
TCT-340 Influence of neoatherosclerosis on long-term outcome of patients with in-stent restenosis treated with paclitaxel coated balloon or everolimus eluting stent: Insights from pooled RIBS IV and V randomized trials.
Authors: Nieves Gonzalo, Carlos Salazar, Maria Perez-Vizcayno, Juan Carlos Gomez Polo, Pilar Jimenez-Quevedo, Jimenez Valero Santiago, Monica Masotti, Rafael Romaguera, Antonio Fernandez-Ortiz, Javier Escaned, Fernando Alfonso, Carlos Macaya
Journal: Journal of the American College of Cardiology (2018)
Rising financial burden of targeted oral anticancer medications on the Medicare Part D program and its beneficiaries.
Authors: Ya-Chen T. Shih, Ying Xu, Fabrice Smieliauskas, Lei Liu
Journal: Journal of Clinical Oncology (2016)

6625 Background: High costs of oncology drugs have threatened the affordability of cancer care. Previous research using data from privately insured non-elderly cancer patients (pts) showed that both the trends of rising prices at launch and of sustained price increase post-launch were more pronounced among targeted oral anticancer medications (TOAMs) compared to targeted intravenous drugs. This study explored the financial burden of TOAMs on Medicare program and beneficiaries. Methods: Using SEER linked to Medicare Part D, 2007-2012, we determined the list of TOAMs from the NCI’s Targeted Cancer Therapy Fact Sheet and identified TOAM users via the National Drug Code in Part D claims. We calculated cost per pt per month (PPPM) by aggregating costs (gross drug costs and out-of-pocket (OOP) payments) of all TOAM claims divided by the total number of months a pt was treated with any TOAM. Results: The study cohort included 37,117 pts who received TOAM between 2007 and 2012. The top five cancers among TOAM users were lung (33%), myeloma (23%), kidney (8%), liver (7%), and leukemia (7%). While the prescription drugs category of medical care consumer price index (CPI) grew at 3.3% per year in the 2007-2012 duration, gross drug costs of TOAMs increased at 11% per year, reaching $7,704 (median $7,636) PPPM in 2012. Among pts who did not receive subsidies from Medicare or other public insurance, OOP costs exhibited a non-linear pattern (Table), with the dip in 2011 corresponding to the starting year of ‘donut hole’ closing. Gross drug costs PPPM varied widely by medication, ranging from $4,100 to > $11,000 in 2012 (not shown in Table). Conclusions: The growth of TOAM costs in Medicare Part D program outpaced the growth of prescription drug CPI more than threefold. Rising drug costs of TOAMs not only impose a substantial fiscal burden on the Medicare Part D program, but also threaten the financial relief that the Affordable Care Act intended to achieve for pts by gradually closing the donut hole. Year Gross drug costs PPPM OOP cost PPPM Mean Median Mean Median 2007 $4,417 $3,494 $1,011 $770 2008 $4,880 $4,011 $1,057 $792 2009 $5,369 $4,465 $1,170 $858 2010 $6,030 $5,216 $1,209 $882 2011 $6,692 $6,208 $709 $494 2012 $7,705 $7,636 $802 $644
PD-L1 expression, tumor mutation burden and response to immune checkpoint blockade in patients with <i>HER2</i>-mutant lung cancers.
Authors: Wei-Chu Victoria Lai, Daniel L. Feldman, Darren J. Buonocore, Edyta B. Brzostowski, Hira Rizvi, Andrew J. Plodkowski, Ai Ni, Joshua K. Sabari, Michael David Offin, Mark G. Kris, Alexander E. Drilon, Maria E. Arcila, Matthew David Hellmann, Bob T. Li
Journal: Journal of Clinical Oncology (2018)

9060 Background: HER2 mutations are present in 3% of lung cancers. Response to immune checkpoint blockade (ICB) in this subset of lung cancers is unknown. We evaluate the landscape of PD-L1 and tumor mutation burden (TMB) in HER2-mutant lung cancers (HER2m) and their response to ICB. Methods: Patients (pts) with advanced HER2m were identified retrospectively. PD-L1 expression was determined by immunohistochemistry (IHC); TMB was estimated by next-generation sequencing (NGS) using MSK-IMPACT. Objective response rate (ORR) to ICB was determined using RECIST v1.1. Kaplan-Meier was used for PFS and OS analyses. Results: We identified 122 pts with HER2m, of whom 87 had PD-L1 IHC and 84 had NGS. 26 pts with known activating mutations in HER2m were treated with ICB. PD-L1 expression was < 1% in 67 (77%), 1-49% in 9 (10%), and ≥50% in 11 (13%) pts. PD-L1 expression was lower when compared to an unselected cohort (n = 578) of lung cancers profiled at our center (p = 0.006). Median TMB (5.7 Mt/Mb, range 0.8-91.8) was the same as the median TMB of an unselected cohort (n = 3000) of lung cancers (p = 0.21). In those treated with ICB, ORR was 12% (3/26, 95% CI 3-30%), including 3 PR, 8 SD, 15 PD. In the 3 responders: none had an HER2 YVMA mutation; 2 (66%) had PD-L1 ≥50%; 2 (66%) had TMB ≥median; median response duration was 3.4 months (range 1.4-21.2); and 1 (33%) remained on treatment with PR. From the start of ICB, median PFS was 1.9 months (95% CI 1.5-4.0), and median OS was 10.4 months (95% CI 5.9-NR). Conclusions: In pts with HER2-mutant lung cancers, PD-L1 expression is lower but TMB is similar to unselected lung cancers. Response to PD-(L)1 blockade is uncommon in pts with HER2-mutant lung cancers, but treatment with ICB can still be considered, particularly in the context of high PD-L1 expression or higher TMB.
Phase I trial of lurbinectedin (PM1183) in Japanese patients with advanced tumors: Results of the dose escalation part.
Authors: Shunji Takahashi, Toshio Shimizu, Toshihiko Doi, Jose Antonio Lopez-Vilariño, Rafael Nuñez, Carmen Maria Kahatt, Carlos Fernandez, Katrin Zaragoza, Hiromi Sasamoto, Arturo Soto-Matos
Journal: Journal of Clinical Oncology (2018)

2551 Background: PM1183 (lurbinectedin, Zepsyre) is a new anticancer agent that inhibits activated transcription, induces DNA double-strand breaks leading to apoptosis and modulates tumor microenvironment. The recommended dose (RD) in non-Japanese patients (pts) is 3.2 mg/m2 on Day 1 every three weeks (q3wk), with reversible myelosuppression as dose-limiting toxicity (DLT). Methods: Japanese pts with solid tumors (excluding CRC or CNS primary tumors), adequate organ function and ECOG PS 0-2 were treated at 3 different dose levels (DLs), 1.5 mg/m2, 2.5 mg/m2 and 3.2 mg/m2, using a 3+3 design. Results: Fifteen pts (10 female / 5 male) were treated and evaluated for safety and efficacy. Median age was 52 years (38-65), albumin 4 mg/dL (3.5-4.6) with 2 median previous lines (1-3). Tumors were, among others, biliopancreatic (3), esophageal (2), endometrial (2) and breast (1). 2 out of 4 pts on DL3 (3.2 mg/m2) had a DLT consisting of a grade (G) 4 neutropenia and a G3 neutropenia lasting > 7 days. Eight pts were treated at the RD established on 2.5 mg/m2, with G2 neutropenia leading to dose reduction and dose delay in 1 pt each. Main adverse events at the RD were hematological with 1 pt (12.5%) presenting G3 neutropenia. Other G3/4 toxicities included a non-drug related G4 hypokalemia (12.5%). Non-hematological toxicities were exclusively G1/2, including G2 ALT increase (50%), AST increase (25%), anorexia (25%), nausea (25%), fatigue (12.5%) and dyspnea (12.5%). At RD, 1 pt (12.5%) with metastatic breast cancer achieved a durable partial response and 3 pts (37.5%) had confirmed stable disease. PK at RD (n= 6 pts) showed a similar behavior to non-Japanese pts, with a mean (standard deviation) total body clearance (CL) of 10.5 (4.5) L/h, half-life of 50.7 (18.1) h and volume of distribution at steady-state of 375.5 (172.0) L. Conclusions: The RD of PM1183 in Japanese pts is 2.5 mg/m2 q3wk, with mild toxicity. Main DLTs were hematological. Hints of activity were observed in breast cancer. Japanese pts showed a similar CL to non-Japanese pts, but with a 26.5% lower distribution volume. A new cohort is exploring PM1183 3.2 mg/m2 (non-Japanese RD) in Japanese pts receiving G-CSF support. Clinical trial information: NCT02210364.
CaMRA-B: Analysing the utility of cardiac magnetic resonance (CMR) imaging as an adjunct to conventional transthoracic echocardiography (TTE) in adjuvant breast cancers treated with anthracycline-based therapy, trastuzumab and left-sided irradiation.
Authors: Deaglan Joseph McHugh, Julie O'Brien, Lorraine Walsh, Zariena Abideen, Rajnish K. Gupta, Linda E. Coate
Journal: Journal of Clinical Oncology (2016)

e21560 Background: Contemporary research has demonstrated that left sided irradiation, anthracycline-based chemotherapy and trastuzumab each pose an independent risk for heart damage. There is however a relative paucity of literature on cumulative cardiotoxicities of these modalities when used in a ‘triple insult’ approach, with the optimal imaging modality for this patient subgroup unknown. With advances in non-invasive CMR imaging, there is a need to re-evaluate the current reliance on left ventricular ejection fraction in determining which patients are at high risk for developing cardiomyopathy Methods: Patients with stage I-III left-sided breast cancer were eligible, provided they were disease free at entry. They must have received definitive surgery, anthracycline-based chemotherapy, trastuzumab and radiotherapy. Patients underwent CMR imaging to assess for bi-ventricular size, morphology, myocardial oedema, post-contrast myocardial hyper-enhancement, valvular dysfunction and left ventricular ejection fraction (LVEF). All patients had a TTE within 12 weeks of CMR imaging. Results: 10 patients were selected. Median age was 47 years (range 34 to 66 years). 70% and 30% of patients received doxorubicin and epirubicin-based chemotherapy respectively. Median time from completion of trastuzumab to CMR imaging was 42 months (range 14-88 months). On CMR imaging, 9 patients had normal biventricular morphology and function with no significant abnormality visualised. 1 patient had a reduced LVEF of 47% with hypokinesis and myocardial thinning of the mid-anterior and apical segments without the presence of scarring or fibrosis, however their TTE was reported as normal, with a LVEF of 62%. Conclusions: The majority of patients showed no evidence of cardiomyopathic changes on CMR imaging, with the exception of 1 patient whose changes were not seen on subsequent TTE. Further prospective studies examining serial imaging as well as matched right sided breast cancer patients are required to determine the role of CMR imaging in these higher-risk patients.