tbuckley/cabot-search huggingface dataset:
Phase ιι (window) preoperative study of olaparib with cisplatin or with durvalumab or alone or no treatment in patients with histologically proven head and neck squamous cell carcinoma who are candidates for surgery (OPHELIA).
Authors: Amanda Psyrri, George Papaxoinis, Panagiota Economopoulou, Ioannis Kotsantis, Vassiliki Kotoula, Onoufrios Tsavaris, Chrysanthi Avgerinou, George Fountzilas
Journal: Journal of Clinical Oncology (2017)

TPS6096 Background: Novel agents are often investigated in unselected end-stage cancer patients and their efficacy is evaluated by the classical RECIST criteria making unlikely to fully exploit the antitumor potential of these targeted agents. Olaparib (O) is a potent inhibitor of PARP especially active in tumors that have homologous recombination DNA repair pathway deficiencies. Durvalumab (D) is a selective, high-affinity human IgG1 monoclonal antibody that blocks PD-L1 binding to PD-1 and CD80, overcoming PD-L1-mediated inhibition of T-cell activation. There is substantial evidence that tumor cells use PARP to repair platinum-induced DNA damage and thus escape apoptosis. In addition, O may complement the antitumor activity of D by increasing DNA damage through repair inhibition. Methods: OPHELIA is an open-label randomized multicenter phase II (window) trial in patients (pts) with head and neck squamous cell carcinoma (HNSCC). Treatment-naive HNSCC pts selected for primary curative study are randomized 3:3:3:1 in 4 neoadjuvant treatment groups: D 1500 mg on day 1 followed by O 600mg daily for 21-28 days (12 pts), cisplatin 60 mg/m 2 on day 1 followed by O 75mg daily for 5 days (12 pts), monotherapy with O 600mg daily for 21-28 days (12 pts) and no treatment (5 pts). Preoperative therapy is discontinued 24 to 36 hours before surgery. Tumor biopsies, CT scans, PET and blood specimens are obtained at diagnosis and at surgery. Primary endpoint is the change in the tumor Ki-67 before and after treatment. Secondary endpoints are objective response rate according to RECIST 1.1 criteria, pathologic complete response rate and metabolic response rate assessed by FDG-PET/CT scan. Exploratory endpoints will include tumor and blood biomarkers. Translational correlates will be tested in tumor tissue, plasma and germline DNA and will include mutations in genes associated with DNA repair assessed by next generation sequencing and circulating tumor cells (CTCs) evaluated for DNA repair biomarkers and PD-L1. Trial is open to enrollment. Clinical trial information: NCT02882308.
Mechanism of acquired resistance to cetuximab in head and neck cancer.
Authors: Arun Khattri, Nizamuddin Sheikh, Rajesh Acharya, Yi-Hung Carol Tan, Sara Kochanny, Mark W. Lingen, Everett E. Vokes, Tanguy Y. Seiwert
Journal: Journal of Clinical Oncology (2018)

e18061 Background: Cetuximab, a monoclonal antibody against EGFR, is the only approved targeted therapy for head and neck squamous cell carcinoma (HNSCC), with a single agent response rate of 13%. Patients (Pt) who respond to the Cetuximab eventually develop resistance. In the present study we present a case report with a deep, sustained response to single agent cetuximab, followed by development of acquired resistance, which was overcome by a different EGFR antibody. Here we report the first known acquired resistance mutation for HNSCC and provide mechanistic validation. Methods: Biopsies of a pt with regional neck recurrence of an oral cavity HNSCC s/p CRT, and progression on platinum-based therapy were collected at three different time points: pre-cetuximab (preCet), acquired resistance to cetuximab (AR-Cet), and acquired resistance to MEHD7945A (AR-MEHD). Biopsies were analyzed using tumor & normal whole exome sequencing (WES) and RNASeq to generate different mutation/expression profiles. Results: A 49yo pt was treated with single agent cetuximab, with a near complete, prolonged response as part of a clinical study (cetuximab vs MEHD7945A). However, the tumor recurred after 9 months with rapid progression (AR-Cet), while still on cetuximab. Pt crossed over to MEHD7945A and showed second deep, sustained response, however after 6 months again developed acquired resistance. WES analysis of preCet and AR-Cet identified an EGFR G465R extracellular domain (ECD) mutation, which affects the cetuximab EGFR binding site. MEHD7945A has a known differential binding site based on crystallographic modeling and was not affected by the AR-Cet mutation. Analysis of AR-MEHD is ongoing. Conclusions: The EGFR ECD mutation G465R confers resistance to cetuximab by altering the binding of Cetuximab to EGFR.This is the first time an ECD mutation has been described as a mechanism of resistance in HNSCC. Switching to a different EGFR monoclonal antibody overcame resistance and should be considered as a strategy for patients with marked initial cetuximab benefit and subsequent acquired resistance using agents with differential binding (e.g. MEHD7945A), or polyclonal anti-EGFR agents (e.g. Sym004).
Prognostic significance of geriatric assessment.
Authors: Beatrice Jara-Almonte Edwards, Xiaotao Zhang, Ming Sun, Juhee Song, Colin P.N. Dinney, Uday R. Popat, Richard E. Champlin, Vicente Valero, Debu Tripathy, Ann-Marie Hedberg, John R Stroehlein
Journal: Journal of Clinical Oncology (2017)

e18140 Background: More than 60% of cancer patients are older adults, and by 2020 the proportion of older adults with cancer will rise to 70%. Objective: To assess risk factors for overall survival (OS) in older cancer patients seen in a comprehensive cancer center. Methods: This is a single center, retrospective cohort study of older cancer patients (65 years of age and older). Patients receiving active cancer care underwent comprehensive geriatric assessment (including cognitive, mood, functional, nutritional, physical, and comorbidity assessment using validated scales). Hematologic, and solid tumors (urologic, breast, gastrointestinal cancers) were evaluated. Targeted interventions were implemented. Analysis: Univariate and multivariable Cox proportional hazards regression analysis were performed to identify factors associated with OS (SAS 9.4). Results: Among 304 eligible patients, the median follow-up was 12.7 months, 98 (32%) died, the median OS was 25.4 months. Median age is 78 years. Univariate analysis revealed known risk factors for mortality (advanced age [p = 0.004], and metastatic disease [p = 0.002]), functional impairment (ADL scores 0-4, p = 0.02), and major depression (p = 0.005). Comorbidity (p = 0.07) and functional impairment showed a marginal significance on OS. Factors with a univariate p-value less than 0.1 were considered in multivariable regression models. A final multivariable model included age group, cancer stage, functional impairment, and major depression. Risk factors for OS include major depression (HR 1.88 (95% CI, 1.12, 3.15), p-value = 0.02), functional impairment (HR 2.47 (95% C.I. 1.28, 4.74), p = 0.007), and metastatic disease (HR 2.2 (95% C.I. 1.30, 3.97), p = 0.004). Conclusions: Major depression and functional impairment were identified as risk factors for OS in older cancer patients. Prospective studies are recommended.
Minority patient reported attitudes regarding tissue donation and participation in cancer research.
Authors: Joanna Roopkumar, Samir Abraksia, Sherry Wilson, Erica Brooksieker, Jennifer J. Griggs, Alok A. Khorana, Davendra Sohal
Journal: Journal of Clinical Oncology (2018)

e18625 Background: Minority populations are underrepresented in biospecimen banks for cancer research. Minority patients’ reluctance to donate biospecimens is a perceived barrier but has not been well studied. We evaluated attitudes among racial/ethnic minority cancer patients toward biospecimen donation and participation in cancer research. Methods: Patients completed a validated 23-item survey [J Cancer Educ, 2014. 29(3): p. 580-7] for this prospective cohort study approved by the Cleveland Clinic IRB. Surveys were provided in the outpatient oncology clinics. Eligibility criteria were: confirmed diagnosis of malignancy, age ≥ 18 years, ECOG PS 0-2, self-reported race/ethnicity as any other than non-Hispanic Caucasian, and undergoing cancer therapy in the next 30 days. Total sample size was 200; data are presented for the entire cohort. Results: The median age of the study population was 63 years (range 28-92); there were 120 (60%) females. The race and ethnicity were predominantly African American (n = 196, 98%) and non-Hispanic (n = 192, 96%) respectively. More than half (n = 128, 64%) were willing to donate samples. A higher proportion (n = 146, 73%) responded as being likely to donate samples if they learned more about research and sample donation. One-third were likely to donate samples if they received money (n = 69, 34%). Only 48 patients (24%) had been asked to donate samples in the past; of those, 38 (79%) had donated. Many (n = 105, 52%) disagreed with negative statements such as, “I will be treated as a guinea pig,” and only 5-10% disagreed with statements such as, “I trust sample banks/medical researchers.” However, 90 patients (45%) endorsed being “concerned that something like the Tuskegee study could happen again.” Conclusions: The majority of patients were willing to donate bio-specimens for research, with a greater likelihood of participation if rationales were provided. However, three-fourths of patients were not approached to participate. Our findings suggest that underrepresentation of minorities in cancer biobanks does not appear attributable to patient reluctance. Community outreach efforts are necessary to ensure equitable representation of minority populations.
Real-world evidence of the effectiveness of adjuvant chemotherapy for early stage breast cancer from Scottish routine data.
Authors: Peter S Hall, Ewan Gray, Joachim Marti, David Brewster, Jeremy Wyatt
Journal: Journal of Clinical Oncology (2018)

e12558 Background: Real world evidence (RWE) has been proposed as a means to address the ‘efficacy-effectiveness gap’ in evidence-based oncology. A major barrier to use of RWE is the perceived lack of internal validity arising from the increased potential for bias compared to evidence generated from randomised trials. This study tested the internal validity of RWE methods applied to estimating to effectiveness of adjuvant chemotherapy for early breast cancer. Methods: Data were obtained from the Scottish cancer registry. All cases of primary breast cancer from 2001 to 2015 were extracted for analysis. Follow-up of vital status until April 2016 was provided by linkage of death records to the cancer registry. Cases meeting the eligibility criteria for adjuvant chemotherapy trials were selected based on age, co-morbidity and prognostic factors. Hazard ratios (HRs) estimating the effectiveness of chemotherapy for preventing breast cancer specific and all-cause mortality, in this trial-eligible group, were calculated using Cox regression on a propensity score matched sample. The HRs were compared with estimates from a published individual patient data meta-analysis of all adjuvant therapy randomised trials. Results: 13,560 trial eligible cases were selected from 56,565 individual records. The primary estimate of the HR for adjuvant chemotherapy for breast cancer specific mortality was 0.679 (95%CI: 0.678, 0.681). In comparison, the meta-analysis reported a HR of 0.64 (95%CI: 0.585, 0.700) for the chemotherapy regimens most commonly used in Scotland during this period. The HR varied between trial-ineligible subgroups. Conclusions: The RWE and meta-analysis of randomised trials provide results that are consistent within an acceptable degree of precision. This suggests RWE estimates of effectiveness have internal validity in the adjuvant therapy setting for early breast cancer. Future studies should consider RWE methods in this setting to address specific gaps in the evidence base provided by clinical trials.
Ibrutinib in association with R-DHAP/ox for patients with relapsed/refractory b-cell lymphoma: Results of the escalating phase of the BIBLOS phase Ib LYSA study.
Authors: Christophe Marc Bonnet, Thierry Lamy, Christophe Fruchart, Steven Le Gouill, Katharina Gunzer, Thomas Gastinne, Fabrice Jardin, Lionel Karlin, Roch Houot, Jehan Dupuis, Herve Tilly, Gilles A. Salles
Journal: Journal of Clinical Oncology (2018)

e19550 Background: Ibrutinib (Ibru) has shown therapeutic activity in patients (pts) with various B-cells malignancies, making it an appropriate drug to combine with R-DHAP/Ox chemotherapy in pts with R/R B-cell non-Hodgkin lymphoma (NHL). In a 1rst escalating phase (EP) (NCT02055924), combining Ibru given from day (d) 1 to 21, we failed to reach a maximal tolerated dose (MTD) able to safely improve R-DHAP/Ox activity. After amendment, the Ibru administration was restricted from d5 to d18. Methods: Pts with R/R B-cells NHL, candidates for autologous transplantation (ASCT), received 3 cycles of R-DHAOx (IC) (oxaliplatin 130 mg/m² on d1) or R-DHAP in association with escalating doses of Ibru at a starting dose (DL1) of 420 mg/d from d5 to d18 with a "3+3" dose escalation design (DL2: 560 mg/d). Dose-limiting toxicities (DLT) evaluated during the 1rst cycle were defined as: grade (Gr) 3-4 non-hematological toxicity; any Gr≥ 2 hemorrhagic events; any Gr≥ 1 intracranial hemorrhage and any Gr≥ 4 hematological toxicity lasting more than 7 d. Results: 12 NHL pts (DLBCL n = 8; FL n = 3; MZL n = 1) have received R-DHAOx associated with Ibru (d5-d18). 1/6 pts treated at DL1 experienced 1 DLT (Gr3 hepatitis). No DLT was recorded for the 6 pts treated at DL2. 11 pts (92%) presented ≥ 1 adverse event, assessed ad serious in 6 pts: Gr≥ 2 thrombocytopenia (2 pts), Gr≥ 2 infection (2 pts), symptomatic atrial fibrillation (1 pt), various Gr≥2 GI and metabolic toxicities (1 pt). Neither severe hemorrhagic event nor rash was observed. 1 pt discontinued Ibru after cycle 1 (hepatitis as a DLT) and 11 pts completed the 3 cycles of IC. All pts received ≥ 80% of the planned dose of Ibru & ≥ 90% of the IC. Pharmacokinetics analysis didn't show any interaction between IC and Ibru. All pts received GCSF injections, 3 (25%) red cells & 9 (75%) platelets transfusions. Treatment response (Cheson 2007) evaluated in 11 pts (92%) was: CR 42% and PR 25%; stem cells were successfully harvested in 10 pts and 7 underwent ASCT. In contrast, Ibru+R-DHAP cohort was interrupted due to DLTs encountered at DL1. Conclusions: Ibru 560 mg/d given from d5-d18 in association with R-DHAOx is safe & actually used in the expansion phase. Clinical trial information: NCT02055924.
Linking tumor mutational load to clinical responses to ipilimumab (IPI) in men with advanced prostate cancer (PCa).
Authors: Sumit Kumar Subudhi, Ana Aparicio, Patricia Troncoso, Jianhua Zhang, Curtis Gumbs, Chang-jiun Wu, Jianjun Gao, Luis M Vence, Jorge M Blando, Paul Gettys Corn, John C. Araujo, Amado J. Zurita, Ina N. Prokhorova, Michael Van Alstine, Christopher Logothetis, Andrew Futreal, James Patrick Allison, Padmanee Sharma
Journal: Journal of Clinical Oncology (2017)

5065 Background: Tumor mutational load and neoantigens have been associated with responses to immune checkpoint therapies in patients (pts) with melanoma and lung cancer. We designed a clinical trial (NCT02113657) in advanced PCa to determine whether the induction of antitumor responses by IPI correlate with T cell responses to PCa neoantigens. Methods: All advanced PCa pts enrolled into this study had sufficient DNA/RNA from tumor tissue obtained prior to receiving IPI (3 mg/kg every 21 days for up to 4 doses) for whole-exosome sequencing (WES) and RNA-seq. Results: Twenty-one of 30 pts have been enrolled. Nine (43%) have received all 4 doses of IPI. IPI was discontinued prematurely in 9 pts (43%) due to drug-related toxicities and in 3 (14%) due to disease progression. All 3 of the latter had liver metastases. To date, tumors from 13 pts have been comprehensively analyzed by WES and RNA-seq. The median time from IPI #1 to the next systemic therapy for these pts was 24 weeks (IQR, 18.3 – 54.3). Responders (R) were defined as pts whose time to next systemic therapy was &gt; 24 weeks. The median time to next systemic therapy for R (n = 7, 54%) is 55 weeks (IQR, 52.0 – 89.0; 2 pts with ongoing responses) versus 18 weeks (IQR, 10.5 – 23.0) for non-responders (NR; n = 6, 46%). In an analysis of all 13 pts, including those with liver metastases, tumor mutational load and frequency of expressed non-synonymous mutations were similar for R and NR pts. However, a subset analysis, excluding pts with liver metastases, revealed &gt; 100 total mutations and/or &gt; 10 expressed non-synonymous mutations in 7/7 R versus 1/4 NR. Conclusions: For advanced PCa pts without liver metastases, tumor mutational load may be associated with responses to IPI. Identification of immunodominant neoantigens may lead to the development of personalized vaccines to be combined with immune checkpoint therapies for the effective treatment of pts with PCa. Clinical trial information: NCT02113657.
Racial disparities impact on endometrial cancer recurrence.
Authors: Ahmed Y. Abdelbadee, Felicia L. Bahadue, Mohamed A. Bedaiwy, Apurva A. Shah, Kristine M. Zanotti
Journal: Journal of Clinical Oncology (2016)

e17111 Background: The relationship of race and endometrial cancer (EC) outcomes is controversial. Published literature documents that EC mortality is 2.5 times more likely in African Americans (AA) than their Caucasian peers. Conflicting data were reported regarding prevalence of obesity, co-morbidities including diabetes, unfavorable histology in AA besides lack of their access to health care services. We aimed to examine impact of race and associated factors on EC recurrence. Methods: Retrospective cohort analysis of EC patients’ records that underwent surgical treatment in University Hospitals Case Medical Center, Cleveland, Ohio from 2008 to 2014 was done. Demographic, Clinical, pathological and surgical data were reviewed. Chi-square tests and t-tests were used to analyze differences between AA and Caucasian patients. Cox proportional hazard model was applied to investigate factors associated with recurrence. Results: Analysis of 258 records was done, 29 (11.2%) were AA. Median follow up was 21 (range; 0 – 78) months. Loco-regional recurrence occurred in 17 (6.6%) patients while distant metastasis occurred in 24 (9.3%) patients. AA patients had significantly more hypertension (89.7% vs. 68.1%, P = 0.02), less pre-operative hemoglobin (12.1±1.4 vs. 13.1±1.5 gm, P = 0.001), more lymph nodes retrieved (21.8±13.2 vs. 14.9±12.7, P = 0.007), heavier uteri (342.7±431.9 vs. 128.9±103.7 gm, P = 0.02), non-endometroid histopathology (46.4% vs. 21.4%, P = 0.003), grade III (51.7% vs. 25.4%, P = 0.003), late FIGO stage [III, IV] (46.4% vs. 16.2%, P = 0.0001), adjuvant therapy (65.5% vs. 40.2%, P = 0.009) and recurrences (37.9% vs. 12.7%, P = 0.0004) than Caucasian patients. There was no significant difference in age, body mass index or diabetes between both races. Multivariate Cox regression analysis revealed that AA race (HR: 2.15, 95% CI: 1.05 – 4.41), grade III (HR: 2.74, 95% CI: 1.35 – 5.56) & FIGO stage III, IV (HR: 4.14, 95% CI: 2.08 – 8.25) were associated with EC recurrence. Conclusions: AA women, grade III histopathology and advanced FIGO stage are at higher risk for EC recurrence. Further research is warranted to better understand the biological mechanisms and genetic differences behind endometrial cancer development in diverse ethnicities.
Pre-clinical evaluation of the PP2A inhibitor LB-100 for the treatment of lapatinib resistant HER2-positive breast cancer.
Authors: Neil Conlon, Martina McDermott, Brigid Browne, Sandra Roche, Fiona O'Neill, Justine Meiller, Alex J. Eustace, Denis Collins, Norma O'Donovan, John Crown
Journal: Journal of Clinical Oncology (2018)

e13021 Background: We have previously shown that protein phosphatase 2A (PP2A) may mediate acquired lapatinib resistance and inhibition of PP2A with okadaic acid enhances lapatinib response in vitro. The aim of this study was to examine the pre-clinical efficacy of LB-100, a PP2A inhibitor, which has recently completed phase I clinical trials (NCT01837667), in models of HER2-positive breast cancer (BC) with acquired resistance to lapatinib. Methods: Proliferation assays were performed to assess sensitivity to lapatinib (L) and LB-100 using acid phosphatase assay and Matrigel 3D growth assay. The effect of PP2A inhibition on the development of acquired L resistance was examined by short term resistance assays using continuous exposure of SKBR3 and HCC1954 cells to L, LB-100 or the combination until L resistance developed. The effect on cell cycle progression and apoptosis was measured by propidium iodide staining and flow cytometry. Crystal violet staining and spectrometer quantification was used to assess cell growth. HCC1954-L cells were implanted in vivo and mice were treated with L and LB-100. Tumours were analysed by immunoblotting for eEF2, p-eEF2 and HER2. Results: SKBR3-L and HCC1954-L cell lines were significantly more sensitive to LB-100 compared to their parental cell lines (IC50 values = 2.12 ± 0.2 µM v 5.38 ± 0.6 µM, and 2.31 ± 0.19 µM v 5.32 ± 0.82 µM, respectively). L plus LB-100 was synergistic in 2D assays in SKBR3-L and HCC1954-L cells (CI values = 0.56 ± 0.13 and 0.68 ±0.26). LB-100 induced apoptosis in SKBR3-L (p = 0.019) and HCC1954-L cells (p = 0.046) and L enhanced apoptosis induction in HCC1954-L cells (p = 0.046). HCC1954-L cells maintained this synergy in 3D conditions (CI value = 0.51 ± 0.07). Short term resistance assays showed that L plus LB-100 blocked the development of L resistance in SKBR3 and HCC1954 cells. L plus LB-100 in combination was well tolerated in vivo and increased intra-tumour p-eEF2 levels (fold change = 68.3) suggesting decreased PP2A activity. Conclusions: This pre-clinical study demonstrates that LB-100 is effective against cell lines with acquired lapatinib resistance, which may translate into clinical efficacy in lapatinib resistant HER2-positive BC.