tbuckley/cabot-search huggingface dataset:
Multicenter phase II trial of palbociclib, a selective cyclin dependent kinase (CDK) 4/6 inhibitor, and cetuximab in platinum-resistant HPV unrelated (-) recurrent/metastatic head and neck squamous cell carcinoma (RM HNSCC).
Authors: Douglas Adkins, Peter John Oppelt, Jessica C. Ley, Kathryn Trinkaus, Prakash C. Neupane, Assuntina Gesualda Sacco, Kevin A Palka, Francis P. Worden, Juneko E. Grilley-Olson, Ronald John Maggiore, Conor Ernst Steuer, Nabil F. Saba
Journal: Journal of Clinical Oncology (2018)

6008 Background: In platinum-resistant RM-HNSCC, the efficacy of cetuximab is modest with a tumor response rate of 13%, median time to progression of 2.3 months and median overall survival (OS) of 6 months (Vermorken JCO 2007). In HPV (-) HNSCC, p16 inactivation and/or CCND1 (cyclin D1) amplification are ubiquitous events that result in hyperactivation of the CDK/cyclin D regulatory complex and Rb inactivation. Deregulated cyclin D1 expression is a mechanism of resistance to EGFR inhibitors. In a phase I trial, palbociclib, a potent CDK4/6 inhibitor, given with cetuximab, was safe and tumor responses were observed in RM HNSCC (Adkins Oral Oncology 2016). Methods: In a phase II trial, patients with platinum-resistant, cetuximab-naive HPV (-) RM HNSCC were treated with palbociclib 125 mg po/d Days 1-21 of 28 day cycles and weekly cetuximab. Platinum-resistance was defined as: progression on platinum in the RM setting; cetuximab-naïve was defined as: no prior cetuximab for RM disease. HPV (-) disease was defined as SCC of the oral cavity, larynx, hypopharynx or p16 negative SCC of the oropharynx. Tumor response assessments (RECIST 1.1) were performed every 2 cycles. We hypothesized that palbociclib and cetuximab would increase the tumor response rate from 13% (historical data with cetuximab) to > 26%. Futility assessments of response and toxicity occurred after every 6 patients (sample size: 30) using a Bayesian monitoring method. Results: 30 patients were enrolled. Median age 67 years (range: 26-84). Sites of recurrence: local/regional (6), distant (8), or both (16). Tumor response occurred in 35% (8 of 23 evaluable to date). Decrease in target lesions occurred in 57% (13 of 23 evaluable). Median progression free survival (PFS) was 6.4 months and median OS was 12.1 months. Immunotherapy was given to three patients before and eight after study participation. Conclusions: Palbociclib and cetuximab resulted in a robust tumor response rate and prolongation of PFS and OS in platinum-resistant HPV (-) RM-HNSCC. The median OS of 12.1 months is the longest reported for patients with platinum-resistant RM HNSCC. Clinical trial information: NCT02101034.
Patterns of care and treatment outcomes of patients with stage I esophageal cancer: A National Cancer Database analysis.
Authors: Amy Catherine Moreno, Ning Zhang, Steven H. Lin, Sharon Hermes Giordano
Journal: Journal of Clinical Oncology (2017)

4035 Background: The aim of this study was to examine current patterns of care and associated outcomes for patients with stage I esophageal cancer (EC) treated in the United States. Methods: The National Cancer Data Base (NCDB) was queried for patients diagnosed with clinical stage T1-2N0 EC from 2004-2012. Patients were categorized into four treatment groups: observation without definitive therapy (Obs), chemoradiotherapy (CRT), local excision (LE), and esophagectomy (Eso). Patient, tumor, and treatment parameters were compared between groups. Kaplan-Meier 5-year overall survival (OS) estimates, postoperative 30- and 90-day mortality comparisons, and multivariate Cox proportional hazards modeling are reported. Results: A total of 5,460 patients met the criteria. Of these, 21% were observed, 14% underwent CRT, 23% LE, and 42% Eso. Median age and follow up were 67 years and 28 months, respectively. Eso was the primary treatment for patients of age ≤ 80 while 48% of patients age &gt; 80 were observed. Age, race, comorbidity score, tumor location within the esophagus, type of medical insurance, median income, type of facility (academic vs. non-academic), and distance from treating facility were significant factors for predicting receipt of local therapy over observation. Postoperative 30-day mortality between the LE and Eso groups was 0.5% and 2.9%, respectively ( P&lt; .001), which increased to 1.4% and 5.5% at 90 days ( P&lt; .001). Five-year OS was 21% for Obs, 26% CRT, 64% LE, and 63% Eso ( P &lt; .001). Multivariate analyses demonstrated improved OS with any form of local definitive therapy: CRT ( HR: 0.54, 95% CI [0.48 - 0.61], P&lt; .001), LE ( HR: 0.24, [0.20 - 0.27], P&lt; .001), Eso (HR: 0.31, [0.28 - 0.35], P&lt; .001). Age, comorbidity score, facility type, distance, median income quartile, and insurance status were also independently associated with OS. Conclusions: Management of stage I EC is influenced by several demographic and socioeconomic factors. Clinical observation yields suboptimal outcomes compared to any local therapy, and a surgical approach should be considered over CRT whenever feasible.
Fertility preservation in female oncology patients: Factors influencing practice patterns.
Authors: Papri Sarkar, Gwendolyn P. Quinn, Anthony Imudia, Susan Thomas Vadaparampil
Journal: Journal of Clinical Oncology (2018)

e22108 Background: Concerns about the impact of cancer therapy on future fertility are valid and fertility preservation (FP) has become a significant component of cancer management. Together with the trend toward delayed childbearing, there are high number of patients diagnosed with cancer before completing their family, necessitating FP. FP options have grown exponentially in the last decade. To serve patients efficiently, it is important to understand FP consult practice patterns. The aim of this study was to explore factors associated with FP counselling among female patients diagnosed with cancer. Methods: A retrospective chart study was performed at Moffitt Cancer Center and University of South Florida between 2006-2013 to examine demographic and medical characteristics and FP counselling discussions including: race, ethnicity, cancer type, insurance coverage, and relationship and parental status. Additionally, discussions of FP options during consult with reproductive endocrinologist were assessed. Results: A total of 125 female patients diagnosed with cancer were referred to fertility consultants for FP counselling. The main diagnosis was breast cancer (44%) followed by 23.2% hematological, 14.4% gynecological, 4% gastrointestinal, 4% sarcoma and other types of cancer (10.4%). The majority of patients (51.2%) had insurance and 48.8% were White. At the time of referral, 40.8% were either married or in a committed relationship. However, only 15.2% had any children. Majority (82.4%) of patients attended an in-person FP consult. During the first FP consult, oocyte freezing was discussed with 51.2% patients. Discussion of embryo cryopreservation was more frequent among patients who had a known sperm donor/partner (40.8%) as compared to 24.8% among patients with unknown sperm donor. Ovarian transposition was discussed with 3.2% patients. Conclusions: Breast cancer patients comprise the majority of patients who seek FP. Patients who have insurance, are White, and in a committed relationship are more likely to pursue FP consult. While providers discussed oocyte preservation with the majority of patients, embryo cryopreservation was more acceptable among patients with a known sperm donor.
Genetic testing and clinical management practices for variants in non-<i>BRCA1/2</i> breast (and/or ovarian) cancer susceptibility genes: An international survey by the Enigma Clinical Working Group.
Authors: Sarah Nielsen, Arcangela De Nicolo, Diana Eccles, Iris L Romero, Susan M. Domchek, Alvaro Monteiro, David Goldgar, Amanda Spurdle, Encarna Gomez Garcia
Journal: Journal of Clinical Oncology (2018)

1539 Background: Advances in massively parallel sequencing technologies have made multigene panels affordable and have revolutionized genetic testing for hereditary breast and ovarian cancer. Through the Evidence-Based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium, we conducted a survey regarding non-BRCA1/2 genes to assess international testing practices and risk management approaches for breast cancer (BC) and ovarian cancer (OC) susceptibility. Methods: Data were collected via in-person and paper/electronic surveys. ENIGMA members from around the world were invited to participate. Additional information was collected via country networks in the UK and in Italy. Results: Responses from 61 cancer genetics centers across 20 countries showed that 16 genes were tested by more than 50% of the centers, but only 6, PALB2, TP53, PTEN, CHEK2, ATM, and BRIP1, were tested regularly. US-based centers tested those genes most often, while UK and Italian centers (not directly affiliated with ENIGMA at the time of the survey) were the least likely to regularly test them. Most centers tested the 16 genes through multigene panels; some centers tested TP53, PTEN and other cancer syndrome-associated genes individually. The majority of centers reported pathogenic variants to patients and would test family members for such variants. Gene-specific guidelines for BC/OC risk management were limited and differed between countries, especially with regard to starting age and type of imaging techniques and risk-reducing surgery recommendations. Conclusions: Only a few genes beyond BRCA1/2 are currently routinely analyzed and related management guidelines are limited and largely based on expert opinion. To achieve clinical application of multigene panel testing through evidence-based management practices, clinicians and patients should be encouraged to participate in international initiatives aimed at sharing information from panel testing, interpreting sequence variants, and collecting prospective data to underpin risk estimates and evaluate the outcome of risk intervention strategies.
Relationship between MRD and PET responses and PFS in previously untreated follicular lymphoma in the GALLIUM trial.
Authors: Judith Trotman, Andrew Davies, Wolfgang Hiddemann, Eva Hoster, Robert Marcus, Christian Schmidt, Chris Harbron, Kirsten Mundt, Tina Nielsen, Christiane Pott
Journal: Journal of Clinical Oncology (2018)

7557 Background: In GALLIUM (NCT01332968; 1202 follicular lymphoma pts), investigator-assessed progression-free survival (PFS) was significantly prolonged by first-line obinutuzumab (G)- vs rituximab (R)-based immunochemotherapy. Lymphoma activity by 18F-FDG PET-CT (PET; Lugano 2014 criteria) showed complete metabolic response (CMR) at end of induction (EOI) to be prognostic for prolonged PFS and overall survival. Minimal residual disease (MRD) negativity in peripheral blood (PB) and/or bone marrow (BM) at EOI was prognostic for prolonged PFS. MRD is a sensitive measure of disease in PB and/or BM, and may add to the prognostic information provided by PET. Methods: Induction with G or R plus bendamustine, CHOP or CVP was followed by maintenance in responders. PET scans at baseline and EOI were assessed by an independent review committee. CMR was defined as a score of 1–3 on a 5-point scale. Baseline PB and BM were screened for MRD by consensus PCR for clonal t(14;18) translocation and/or Ig variable domain rearrangement. MRD at EOI was positive if allele- or translocation-specific real-time quantitative or nested PCR were positive in PB or BM. Results: Median follow-up was 44 months. At baseline, 595/609 pts with PET scans had detectable lesions and 815/1101 with MRD evaluable samples had a suitable MRD marker; 298 were evaluable for both at EOI. CMR was seen in 266 pts; 250 of these were MRD-negative (Table). For these pts, 2.5-year PFS from EOI was 85% (95% CI: 80–89). This group had the best PFS: Cox proportional hazard ratio (HR)=0.39 (95% CI: 0.17–0.93; p=0.03) vs CMR + MRD-positive; and HR=0.39 (95% CI: 0.19–0.81; p=0.01) vs non-CMR + MRD-negative. There were too few non-CMR + MRD-positive pts for analysis. Conclusions: Most evaluable pts achieved CMR and MRD-negativity, with a minority progressing despite a favorable prognosis. Risk of progression or death in pts achieving only CMR or MRD-negativity was 2.5-fold greater than in pts who achieved both, suggesting that EOI PET and MRD responses could provide complementary information. Clinical trial information: NCT01332968.PET Response MRD Status Negative (%) Positive (%) All (%) CMR 250/298 (84) 16/298 (5) 266/298 (89) Non-CMR 24/298 (8) 8/298 (3) 32/298 (11) All 274/298 (92) 24/298 (8) 298/298 (100)
Uridine triacetate as an effective antidote in preclinical models of 5-FU overdoses and impaired 5-FU clearance.
Authors: Reid von Borstel, Rolando Garcia, Joel A. Saydoff, Michael K. Bamat
Journal: Journal of Clinical Oncology (2016)

e18232 Background: Oral uridine triacetate improves survival and reduces toxicity when administered after serious overdoses of 5-fluorouracil (5-FU) in preclinical animal models and in humans. It acts by delivering systemic uridine, which counteracts toxic incorporation of fluorouridine triphosphate (FUTP) into RNA. However, the maximum time window for administration of uridine triacetate after 5-FU for effective prevention of mortality has not been established in animals; and additionally, uridine triacetate efficacy has not been characterized in models of impaired 5-FU clearance that mimic genetic DPD deficiency. The purpose of this study was to investigate the optimum dosing of uridine triacetate relative to 5-FU administration in order to ameliorate toxic effects of 5-FU in lethal models of 5-FU overdose and impaired 5-FU clearance. Methods: Mouse models of lethal acute 5-FU overdose and of a 5-FU clearance defect (DPD inhibition with 5-ethynyluracil) that made a standard therapeutic dose lethal were developed. Uridine triacetate dosing mimicking pharmacokinetics of the clinical regimen was initiated at different times after 5-FU in both models to establish a treatment time window. Results: The MTD of 5-FU in BALB/c mice was 100 mg/kg/week ip. A single 300 mg/kg dose of 5-FU was lethal in all control animals. Uridine triacetate (2000 mg/kg q8h x15 po) initiated 24, 48, 72 and 96 hr after 5-FU resulted in 90, 60, 30 and 20% complete recovery and long-term survival. 100 mg/kg 5-FU given with the DPD inhibitor 5-ethynyluracil (2 mg/kg) was lethal in all control mice. Uridine triacetate initiated 24, 48, 72 and 96 hr after 5-FU resulted in 80, 40, 50 and 20% recovery and survival. Earlier initiation of uridine triacetate within a 96 hr window in both models improved survival, and reduced hematologic and GI toxicity (histology and body weight changes) among survivors. Conclusions: Uridine triacetate was an effective antidote in lethal models of both 5-FU overdose and clearance defects, with a treatment time window of approximately 96 hours after 5-FU, concordant with human clinical experience after overdoses and early onset of serious toxicities after capecitabine or 5-FU.
Agreement about end-of-life (EOL) care among advanced cancer patients and their caregivers: Associations with care received.
Authors: Charles Stewart Kamen, Paul Duberstein, Holly Gwen Prigerson, Supriya Gupta Mohile, Matthew Asare, Michelle Christine Janelsins, Karen Michelle Mustian, Luke Joseph Peppone, Ronald M. Epstein
Journal: Journal of Clinical Oncology (2017)

10021 Background: Patients with advanced cancer and their caregivers often have different preferences regarding patients’ EOL care. Disagreement in a patient-caregiver dyad can increase stress and result in suboptimal care. Understanding factors that promote agreement, as well as the effect of agreement on care received at EOL, can inform interventions to improve communication and EOL decision-making for patients and caregivers. Methods: 205 patients (Stage III or IV cancer plus limited prognosis) and their caregivers were recruited to a randomized controlled trial of a communication intervention for patients, caregivers, and providers (Cancer Communication Study, PI: Epstein). Before intervention, patients completed the Preferences for Life-Extending Treatment questionnaire, which asked their preference regarding experimental treatment, life support, and palliative care; caregivers were asked about patients’ preferences. Binomial logistic regressions analyses modeled agreement in preferences as a function of patient and caregiver demographic characteristics and EOL care received as a function of patient-caregiver agreement. Results: The majority of patient-caregiver dyads agreed about experimental treatment (60.3%), life support (63.4%), and palliative care (70.7%). Dyads were more likely to agree about palliative care when patients were female (OR = 1.94, p = .03) and non-Hispanic white (OR = 2.10, p = .07) and when caregivers were college educated (OR = 2.04, p = .03). Of the 82 patients who died during study follow-up, 57 (69.5%) received EOL care congruent with their preferences. In 19 of the 38 (50%) cases where patient-caregiver dyads disagreed, caregivers’ preferences predicted EOL care received. Dyadic agreement about life support was associated with increased odds of patients receiving/not receiving life support congruent with their preference (OR = 3.02, p = .02). Conclusions: Facilitating agreement between patients and caregivers could improve receipt of patient-centered care. A communication intervention designed to increase dyadic agreement by helping patients and caregivers discuss challenging EOL decisions might improve EOL care delivery. Clinical trial information: NCT01485627.
Clinical relevance of Vav3.1 expression in ovarian cancer and involvement in mechanisms causing genuine multi-drug resistance.
Authors: Daniel Uwe Reimer, Maximilian Boesch, Sieghart Sopper, Dominik Georg Friedrich Wolf, Anouk Gaber-Wagener, Jiri Hatina, Christian Marth, Alain G Zeimet
Journal: Journal of Clinical Oncology (2018)

e17528 Background: Platinum resistance is a major obstacle for sufficient treatment of ovarian cancer and exact mechanisms of platinum resistance are far from being fully understood. Vav3 is a key modulator of GTP-hydrolases of the Rho/Rac family crucially involved in cell proliferation. Vav3 is alternatively spliced in full-length Vav3-alpha and N-terminal truncated Vav3.1 lacking its self-regulatory domains. The aim of this study was to estimate the clinical impact of Vav3 and all other Vav family members in ovarian cancer. Methods: Purification of cancer stem cells (CSCs) from different ovarian cancer cell lines was performed by flow cytometry/FACS. Differences in gene expression between CSCs and Non-stem cells were assessed by Gene Array analysis and confirmed by RT-PCR and immunoblot. In addition, Vav mRNA expression was determined in 150 epithelial ovarian cancers. Clinicopathological parameters, platinum-sensitivity and survival were analyzed and associated to Vav expression. Clinical results were validated in an independent patient collective including 150 high-grade serous cancer specimens from the TCGA database. Results: CSCs exhibited marked overexpression of Vav3.1 (P < 0.001). Vav1 and Vav2 did not prove to be of clinicopathologic relevance in ovarian cancer. High Vav3.1 expression correlated with higher FIGO stage and residual disease. Furthermore, Vav3.1 overexpression was associated with poor progression-free (HR = 2.820, P = 0.0001) and overall survival (HR = 2.842, P = 0.0001). Subgroup analyses revealed an impact of Vav3.1 on survival in type-II but not in type-I cancers. Notably, platinum-refractory cancers showed marked overexpression of Vav3.1 compared to other subsets of platinum-sensitivity (15.848 vs. 6.653, P = 0.0001). These results were corroborated in the TCGA collective. Conclusions: We herein show that the N-terminal truncated Vav3.1 isoform is over-expressed in multi-drug resistant stem-cell like fractions of ovarian cancer cells. We further demonstrate its clinical impact in terms of prognosis and its marked over-expression in cancers with genuine but not acquired platinum resistance.
A major response to carboplatin in a metastatic triple-negative breast cancer patient with somatic mutation of BRCA1 and RAD51B: When chemotherapy meets precision medicine
Authors: L. Seguin, M. Chaffanet, R. Sabatier, A. Jose, S. Garnier, N. Carbuccia, A. Guille, D. Birnbaum, F. Bertucci, A. Goncalves
Journal: Annals of Oncology (2018)

Background: Recent clinical data indicate a higher pathological complete response rate when platinum is added to neoadjuvant chemotherapy in triple-negative breast cancer (TNBC), and favorable outcomes have also been observed in metastatic TNBC patients treated with platinum-based regimen. BC associated with germline BRCA mutations display DNA double-strand break repair defects, which are thought to render them particularly sensitive to DNA repair targeting drugs such as PARP inhibitors and/or platinum analogs. In addition, BRCA1/2 genes promoter methylation, somatic mutation, as well as other genomic alterations in DNA repair genes may also drive homologous recombination-deficiency (HRD) and the so-called "BRCAness" phenotype. Yet, their association with sensitivity to platinum derivatives or PARP inhibitors in BC remains discussed. Methods: A 75-year old women with rapidly progressive metastatic TNBC and clinical resistance to anthracylines, taxanes, capecitabine, pembrolizumab and eribulin was enrolled in a molecular profiling program (PERMED trial, NCT02342158). To identify clinically-actionable gene mutations and putative druggable pathways, a pretreatment biopsy of liver metastatic tissue was obtained and analyzed by whole genome array-CGH (aCGH) and targeted next-generation sequencing (NGS) of 559 cancer genes, along with germline sequencing. Gene copy number aberrations (CNAs) and somatic mutation status that could help therapeutic decision were examined. Results: No germline BRCA mutation was found. The aCGH analysis showed a genomic instability associated with a BRCAness profile and an HRD score of 19. The CNAs analysis showed a focal homozygous loss of RAD51B/RAD51L1 gene, while NGS identified a somatic mutation of BRCA1. Patient received carboplatin single-agent and developed a durable and almost complete response. Conclusions: These data strongly suggest that carboplatin may be highly effective in advanced TNBC with no germline BRCA mutation but somatic genomic alterations disrupting DNA repair pathways, supporting precision medicine trials evaluating platinum derivatives in this setting. Legal entity responsible for the study: Institut Paoli Calmettes. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.