tbuckley/cabot-search huggingface dataset:
Recurrence of ovarian cancer in <i>BRCA</i>wt patients without maintenance therapy: Real-world evidence.
Authors: Melinda Louie-Gao, Ebru Aydin, Premal H. Thaker
Journal: Journal of Clinical Oncology (2019)

5547 Background: Development of platinum resistance is a major clinical challenge in ovarian cancer (OC) treatment. In the phase 3 ENGOT-OV16/NOVA trial of the poly(ADP-ribose) polymerase inhibitor (PARPi) niraparib, 55% of BRCA wild-type ( BRCAwt) patients (pts) receiving placebo developed platinum resistance after their last platinum-based therapy (ie, progressive disease within 6 months of their last chemotherapy [CT] dose). Niraparib, a PARPi approved for the maintenance treatment of adult pts with recurrent OC following platinum-based CT, significantly prolongs progression-free survival (PFS). This real-world data analysis investigated the risk of platinum eligibility loss for BRCAwt pts who did not receive maintenance therapy after platinum treatment. Methods: This retrospective study identified 5,535 pts with OC from January 2011–October 2018 using data from Flatiron, a longitudinal, demographically and geographically diverse database derived from records of &gt; 265 cancer clinics and &gt; 2 million US cancer pts. BRCAwt pts who had received ≥2 lines of platinum-based CT, had disease progression ≥6 months after their previous line of therapy, and had no maintenance therapy (PARPi, bevacizumab, or CT agents) after their current treatment were included. Kaplan-Meier analysis was used to estimate the probability of pts initiating next treatment or death, whichever occurred first, within 6 months. Results: Of 5,535 pts diagnosed with OC, 147 BRCAwt pts met the inclusion/exclusion criteria of this analysis (similar to ENGOT-OV16/NOVA placebo arm). An estimated 56% of pts received the next treatment or died within 6 months after their last platinum-based therapy. Median time to next therapy or death was 5.1 months (95% confidence interval, 3.1–7.2). Conclusions: Our real-world data analysis shows that 56% of BRCAwt pts who received platinum-based treatment without maintenance therapy had recurrent OC within 6 months, classifying them as platinum resistant. Use of maintenance treatment options, such as niraparib, has been shown to significantly prolong PFS after platinum-based CT and may be beneficial in extending the platinum-free interval, enabling pts to remain eligible for further platinum therapy.
Metformin use and pancreatic cancer survival in U.S. veterans with diabetes mellitus: Are there racial differences?
Authors: Adetunji T. Toriola, Suhong Luo, Theodore Seth Thomas, Bettina F. Drake, Su-Hsin Chang, Kristen Marie Sanfilippo, Kenneth Robert Carson
Journal: Journal of Clinical Oncology (2019)

4129 Background: Experimental and observational studies suggest that metformin holds promise in improving survival among pancreatic cancer patients. However, findings from prior observational studies have been questioned because most did not control for immortal time bias, which can overestimate the survival benefit of a drug. In addition, previous studies did not present data on African American patients. Thus, it is unknown if any survival advantage from metformin extends to African Americans. To address these limitations, we analyzed data from the U.S. Veterans Health Administration (VHA). Methods: A population-based retrospective cohort study of 3,811 (N = 773 are African Americans) pancreatic cancer patients with pre-existing diabetes mellitus diagnosed within the VHA between October 1, 1998 and December 30, 2010, and followed until December 2014. We calculated hazard ratios (HR) and 95% confidence intervals (CI) using both the time-varying Cox proportional hazards regression model, which controls for immortal time bias, and conventional Cox model. Analyses were adjusted for confounders. We also stratified analyses by race. Further, we performed analyses among patients who were metformin naïve (N = 1158) at the time of pancreatic cancer diagnosis (most representative of patients enrolled in clinical trials). Results: Median survival was 4.5 months among metformin users versus 3.7 months among non-users. Metformin use was not associated with pancreatic cancer survival in analysis using the time-varying Cox model: HR = 1.05 (95% CI 0.92-1.14, P-value = 0.28). Results were identical among non-Hispanic Whites and African Americans. In analysis using conventional Cox model, metformin use was associated with an artificial survival benefit: HR = 0.89 (95% CI 0.83-0.98, P-value = 0.01). Among patients who were metformin naïve at the time of pancreatic cancer diagnosis, metformin use was associated with improved survival in analysis using the time-varying Cox model: HR = 0.77 (95% CI 0.61-0.98, P-value = 0.03). The HRs were 0.78 (95% CI 0.61-0.99, P-value = 0.04) among non-Hispanic Whites and 1.20 (95% CI 0.75-1.93, P-value = 0.45) among African American patients. Conclusions: We observed no associations between metformin use and pancreatic cancer survival. Nevertheless, we noted improved survival (limited to non-Hispanic White patients) among patients who were metformin naïve at the time of pancreatic cancer diagnosis, which requires conformation in other studies.
A randomized phase III trial comparing dose-dense epirubicin and cyclophosphamide (ECdd) followed by paclitaxel (T) with paclitaxel plus carboplatin (PCdd) as adjuvant chemotherapy for early triple-negative breast cancer patients with high-recurrence risk.
Authors: Jiani Wang, Qing Li, Yuxin Mu, Tongtong Zhang, Ying Han, Jiayu Wang, Qiao Li, Yang Luo, Peng Yuan, Fei Ma, Ying Fan, Pin Zhang, Binghe Xu
Journal: Journal of Clinical Oncology (2019)

528 Background: There are no well-established adjuvant chemotherapy (AC) regimens for early triple negative breast cancer (TNBC). Our randomized phase III trial was designed to compare dose dense paclitaxel plus carboplatin (PCdd) with commonly used dose dense epirubicin and cyclophosphamide, followed by paclitaxel (ECdd-T) regimen as AC for TNBC with high recurrence risk. Methods: Between May 2011 and November 2015, TNBC patients were randomized in 1:1 ratio to receive PCdd or ECdd-T regimen as AC every two weeks for 8 cycles with administration of granulocyte stimulating factor (G-CSF) support. The primary endpoint was 3-year disease free survival (DFS).The secondary endpoints included overall survival (OS) and safety. Survival analyses were also performed for different subgroups stratified by age status (≤40 years vs &gt;40 years), Ki 67(&lt;50 vs ≥50), tumor size (&lt;2cm vs ≥2cm), nodal status (N- vs N+) and treatment free survival (TFS) (&lt;30 days vs ≥30 days). Results: In total, 132 patients with a median age of 49 years (PCdd 64 patients, ECdd-T 68 patients) were enrolled. After a median follow-up of 57.3 months, 23 events were observed (18 in ECdd-T, 5 in PCdd). Patients in the PCdd arm had significantly higher DFS rate than that in the ECdd-T arm (log-rank p = 0.0046, hazard ratio (HR) 0.305, 95% confidence interval (CI) = 0.134-0.693). The 3-year DFS rate was 93.7% with PCdd versus 77.9% with ECdd-T,respectively. Difference in 3-year OS rate was observed between the two arms (98.4% vs 92.6%), significantly higher in the PCdd arm ( p = 0.0268). Both regimens were well tolerated with manageable adverse events(AEs). Worse neutropenia (Grade 3/4: 48.5% in ECdd-T vs. 21.9% in PCdd, p=0.002) was found in ECdd-T arm. 3-year DFS rate for PCdd was superior in the following subgroups, age&gt;40 years, clinically evaluated lymph nodes, TFS &lt;30 days, with statistical significance ( p &lt;0.05). Conclusions: Our data suggested that PCdd was superior to ECdd-T as AC for early TNBC in terms of improving 3-year DFS and OS. PCdd with lower hematological toxicity might be an appropriate regimen for early TNBC patients with high recurrence risk. Clinical trial information: NCT01378533.
Results of a phase 2 trial of ribociclib and letrozole in patients with either relapsed estrogen receptor (ER)-positive ovarian cancers or relapsed ER-positive endometrial cancers.
Authors: Gerardo Colon-Otero, S. John Weroha, Valentina Zanfagnin, Nathan R. Foster, Erik Asmus, Andrea Elisabeth Wahner Hendrickson, Aminah Jatoi, Matthew Stephen Block, Carrie L Langstraat, Gretchen Elizabeth Glaser, Tri Dinh, Matthew Robertson, John Kelly Camoriano, Kristina Butler, John A. Copland
Journal: Journal of Clinical Oncology (2019)

5510 Background: Single agent aromatase inhibitor (AI) therapy is associated with limited clinical activity in ovarian cancer (OC) and endometrial cancers (EC). AI therapy was associated with a progression free survival (PFS) at 12 weeks of only 20% in relapsed OC (Bowman et al, 2002) and a median PFS of 1 month in relapsed EC (Rose et al, 2000). In Estrogen Receptor (ER) positive metastatic breast cancer, clinical studies had shown a significant prolongation of PFS with the addition of the cyclin kinase 4/6 inhibitor ribociclib to AI (Hortobagyi et al, 2016). Here, we report the results of a phase 2 clinical trial of the combination of ribociclib and letrozole in patients with relapsed ER positive OC or EC. Objectives: Primary endpoint was the proportion of patients with relapsed ER positive OC or EC alive and progression-free after 12 weeks of therapy (PFS12) with the combination of ribociclib given at a dose of 400 mg orally daily and letrozole 2.5 mg orally daily. A PFS of 45% was considered a favorable result based on the data referenced above from Bowman et al. Methods: Eligibility criteria included patients with relapsed ER positive OC or EC, with measurable disease, not previously treated with ribociclib or AIs. Xenografts were created from CT guided tumor biopsies at baseline to assess feasibility. Results: A total of 40 patients were enrolled (20 with OC and 20 with EC) ) with a median age of 61 years (range: 30-82) and 64.5 (range: 52-75) in the OC and EC groups respectively. Among the OC patients, 17 had high grade serous carcinomas and 3 had low grade serous carcinomas. 11 EC patients had endometrioid cancers (3 with grade 1 tumors) and 9 had high grade serous tumors. Ten out of 20 OC patients and 11/20 EC patients were alive and progression-free at 12 weeks (PFS12 of 50 and 55%, respectively). The most common grade 3 or higher adverse events (occurring in at least 5 pts) were leukopenia (18%), lymphopenia (18%), neutropenia (13%), and fatigue (13%). 34 tumor biopsies were suitable for injection into mice and 44% engrafted. ER expression persisted through multiple passages in mice. Two of three EC PDX models exhibited improved PFS with letrozole/ribociclib compared to letrozole alone. Conclusions: The combination of ribociclib and letrozole is associated with a promising 50% and 55% PFS12 in patients with ER positive relapsed OC or EC respectively. Creation of xenograft tumor models from CT guided biopsies of OC and EC tumors was feasible. Clinical trial information: NCT02657928.
The mutational profile analysis of extramural vascular invasion in rectal cancer.
Authors: Mingtian Wei, Yane Song, Xiangbing Deng, Lijia Wu, Wenjian Meng, Wanning Yang, Beibei Mao, Ying Yang, Wenbo Han, Henghui Zhang, Ziqiang Wang
Journal: Journal of Clinical Oncology (2019)

e15128 Background: Extramural vascular invasion(EMVI) is a known independent predictor of poor prognosis in rectal cancer, as evidenced by a higher risk of developing metastases and a shorter DFS compared with negative tumours. However, the molecular mechanisms of EMVI genesis remains unclear. The objective of this study is to clarify the distinct molecular characterization of EMVI-positive tumours from that of EMVI-negative tumours. Methods: DNA was extracted from FFPE tumor specimens and matched normal tissue samples from rectal cancer patients who underwent surgical resection. Comprehensive genomic profiling analysis was performed using a 2.41M size panel covering exon regions of 1,622 genes based on next generation sequencing assay. Somatic Mutations were analyzed to determine the difference of molecular features between EMVI-positive and EMVI-negative patients. Results: In this retrospective study, a total of 48 rectal cancer patients without distant metastases were included: 17 patients in the EMVI-positive group and 31 patients in the EMVI-negative group. All the EMVI-postive patients had lymph node metastasis and 15 patients had lymph node metastasis in EMVI-negative group. Among all the tumours, the most frequently mutated genes were TP53, APC, KRAS, SMAD4, CHEK2, TCF7L2 and FBXW7. Mutations of TCF7L2 and CHEK2 were more frequently observed in EMVI-positive tumours than that in EMVI-negative tumours with p &lt; 0.05. Survival analysis (Kaplan-Meier) indicated that patients with KRAS mutations(n = 9) had a shorter DFS than patients without KRAS mutations(n = 23) in patients with lymph node metastasis (p &lt; 0.05). In addition, age was significantly associated with DFS according to the survival analysis (p &lt; 0.05). Conclusions: Several possible candidate genes that may be helpful to characterize the distinct mutational profile of EMVI-positive tumours from EMVI-negative tumours were identified, which may be of great significance in disclosing the molecular mechanism underlying in EMVI initiation and progression. Expanded prospective cohorts are warranted to further elucidate these findings.
Unlocking PARP inhibitor efficacy for HRD-negative cancers using the alphalex tumor targeting platform inhibitor efficacy for HRD-negative cancers using the alphalex tumor targeting platform.
Authors: Ranjit Bindra, Ranjini K Sundaram, Robert J Aiello, Dan Marshall, Patricia Bourassa, Johanna Csengery, Qing Zhang, Brett Robinson, Lori lopresti-Morrow, Jane Bechtold, Laurie Tylaska, Tim Paradis, Vishwas Paralkar, Per Hellsund, Peter Glazer
Journal: Journal of Clinical Oncology (2019)

e14664 Background: Poly(ADP-ribose)polymerase inhibitors (PARPi’s) are a promising new class of anti-cancer agents, but their clinical application has largely been limited to tumors with homologous recombination deficiency (HRD), such as those with BRCA1/2 mutations. One strategy to target HRD-negative tumors with PARPi’s is to combine them with chemotherapy, although clinical trials indicate that dose-limiting toxicities are a major barrier to achieving synergistic efficacy with these combinations. Methods: We sought to test the hypothesis that HRD-negative cancers can be effectively treated with tumor-targeted PARPi’s in combination with chemotherapy, using our recently developed alphalex platform. This platform allows small molecule anti-cancer agents to penetrate cell membranes only at the low pH associated with the tumor microenvironment and tumor cells, directly delivering drugs to tumors while sparing normal tissue. We tested whether alphalex PARPi-conjugates in combination with chemotherapy could selectively kill cancers independent of HRD status, using a range of in vitro and in vivo tumor models. Results: We conjugated a diverse range of structurally unique PARPi’s using the alphalex platform, and demonstrated that these molecules are delivered directly into tumor cells in a pH-dependent manner. We observed significant reductions in PARylation activity and exquisite synergy with DNA damaging agents in vitro. We then demonstrated that alphalex-PARPi conjugates in combination with both temozolomide (TMZ) and irinotecan induce significant tumor cell killing in HRD-negative tumors in vivo. Importantly, we found that our tumor-targeting approach significantly reduced normal tissue toxicity, with almost complete sparing of the bone marrow relative to TMZ alone. Conclusions: The alphalex platform enables PARPi combinations with clinically relevant chemotherapies, as a means to target HRD-negative cancers without significant bone marrow toxicity. Based on these successful proof-of-concept data, we are now performing IND-enabling studies for an alphalex PARPi conjugate (CBX-11), and we anticipate initiating a Phase I clinical trial in January 2020 in solid tumors independent of HRD status.
Evaluating gender as a predictive marker for response to bevacizuamb (Bev) in metastatic colorectal carcinoma (mCRC): Pooled analysis of 3369 patients (pts) in the ARCAD database.
Authors: Ofer Margalit, William S. Harmsen, Einat shacham-Shmueli, Molly Petersen, Ben Boursi, Leonard B. Saltz, Richard Adams, Tim Maughan, Jean-Yves Douillard, Eric Van Cutsem, Herbert Hurwitz, Carsten Bokemeyer, Niall C. Tebbutt, Fairooz F. Kabbinavar, Aimery De Gramont, Qian Shi, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2019)

3539 Background: Previous studies suggest a possible gender-specific response to Bev in mCRC, showing a benefit in males, while the effect in females is less significant. Therefore, we evaluated response to Bev according to gender. Methods: Data from 3369 mCRC patients enrolled on 4 first-line randomized trials testing Bev (2000-2007) were pooled. Association between gender and progression-free survival (PFS)/overall survival (OS) was evaluated by stratified Cox regression model, adjusted for potential confounders. Predictive value was evaluated by interaction (inter.) effect between gender and treatment. In a pre-planned secondary analysis, analyses were stratified using an age cut-point of 60 years (commonly used in breast cancer trials) to evaluate the possible role of menopausal-related effects. Results: OS was not statistically different between males and females (median OS [mOS], 18.8 vs. 17.6 months [mo], adjusted hazard ratio [HR adj ], 0.93, 95% confidence interval [CI], 0.84-1.03, p, 0.15) in the overall population. Bev was associated with an improved mOS in males and females, with a 2.3 and 0.6 mo benefit, respectively, as well as an improved PFS. There was no statistically significant interaction effect between gender and treatment (see table). Further stratified by age (&lt; vs. ≥ 60 years), Bev resulted in improved PFS and OS in both genders, at all ages, except for the effect in young females which did not reach statistical significance (see table). Conclusions: Our results confirmed the mOS benefit from addition of Bev to first-line chemotherapy in mCRC in both genders, although the benefit in females was &lt; 1 month. For females under the age of 60, there are uncertainties for mOS benefit from addition of Bev and further evaluation is needed. [Table: see text]
Bladder Cancer Multidisciplinary Clinic (BCMC) model: Impact on imaging, pathology and treatment recommendations.
Authors: Brian Winters, Leonidas Nikolaos Diamantopoulos, Maria S. Tretiakova, Lawrence D. True, Jean H Lee, Jing Zeng, Jay Justin Liao, Heather H. Cheng, Michael Thomas Schweizer, Andrew Caleb Hsieh, Evan Y. Yu, George R Schade, John L. Gore, Daniel W. Lin, Manjiri Dighe, Funda Vakar-Lopez, Kenneth J. Russell, Petros Grivas, Robert B. Montgomery, Jonathan L. Wright
Journal: Journal of Clinical Oncology (2019)

4537 Background: Despite guideline-based standard of care recommendations in BC and upper tract urothelial carcinoma (UTUC), treatment remains variable across US. Experts recommend focusing BC care in tertiary centers. We hypothesized that a BCMC model, with expert central pathology and radiology review, may result in changes in corresponding reports, and, thus, treatment recommendations. Methods: Our BCMC clinic format includes simultaneous consultation with Urologic, Medical and Radiation Oncology, with real time expert genitourinary pathology and radiology review. We retrospectively assessed the concordance between outside (pre-BCMC) imaging &amp; pathology review and BCMC review. Differences between pre- and post- BCMC recommendations on management were also assessed; descriptive statistics were used. Results: We identified 233 BC/UTUC patients (pts) referred to BCMC. Complete radiographic and pathologic data were available for 209 pts. Median age at time of evaluation was 68 (27-93) and 85% were PS ECOG 0-1. After BCMC review of outside records, 112 (53.6%) imaging and/or pathology changes were noted, with 57 (27%) pts upstaged. Overall, imaging interpretation was changed in 25% of cases, and 20% of pts were upstaged. BCMC pathology review resulted in changes in 59 (28%) pts. Among those, 42 (71%) had histologic subtype addition or change, 9 (15%) had LVI/CIS status change, and 2 (3.4%) had low to high grade conversion. In terms of pathology staging, 7 (12%) were downstaged, and 5 (8.5%) upstaged. Further diagnostic work-up was recommended in 71/209 (34%) pts, resulting in upstaging in 11/71 (15.5%) of cases. Pre- and post- BCMC-recommended treatment modality differed in 55/209 (26%) pts, while a new treatment modality was added in 28/209 (13%) pts. These recommendations were followed 91.4% of the time (191/209 pts). Conclusions: BCMC initiation at our institution resulted in imaging and/or pathology diagnostic changes in almost half of cases, with approximately a quarter of pts being upstaged. Findings reveal the importance of expert radiology and pathology review in BC. Further study is needed to confirm the proposed benefits and impact of BCMC on treatment response and outcomes.
A clinical prognosis model for Asian advanced melanoma patients receiving immunotherapy.
Authors: Xuan Wang, Xieqiao Yan, Zhihong Chi, Lu Si, Xinan Sheng, Yan Kong, Lili Mao, BIN LIAN, Bixia Tang, Li Zhou, Chuanliang Cui, Jun Guo
Journal: Journal of Clinical Oncology (2019)

e14081 Background: Immunotherapy PD-1 inhibitor therapy shows relative lower efficacy in Asia especially in acral and mucosal subtypes. The identification of predictive factors of immunotherapy remains a crucial but unmet clinical need. The objective of this study was to evaluate advanced melanoma patients treated with anti-PD-1 in order to identify risk factors for PFS, OS and develop a prognostic scoring system for immunotherapy. Methods: Patients with unresectable melanoma treated with PD-1 inhibitor enrolled on trials between 2015 and 2017 at Peking University Cancer Center were included. A nomogram to predict survival was developed based on a multivariable Cox model. The predictive performance of the model was assessed according to the C-statistic, Kaplan–Meier curve and calibration plots. Results: The discovery cohort comprised 133 patients with unresectable melanoma. 38.3% acral and 21.8% mucosal melanomas were included, 26.3% with liver metastases, 31.6% with an elevated serum LDH, 20.3% harbored BRAF mutations. The median PFS was 4.8 months, based on the Cox model, four factors were selected for the nomogram and assigned specific scores: tumor metastases number≥3, 1; tumor size≥80 mm,1; LDH level, 1 (higher limit of normal range); liver metastases,1. The model achieved relatively good discrimination and calibration, with a C-statistic of 0⋅804 (Table). BRAF mutations were associated with shorter PFS in univariate analysis but not in multivariate analysis. Subtypes were also not related to PFS in this cohort. The median OS was 22.8 months. Univariate analysis identified eight factors were associated with significantly worse OS among 21 factors ( BRAF and subtype included, which not found as risk factors). Based on the Cox model, five factors were selected for the nomogram and assigned specific scores: ECOG &gt; 1, 0.6; Hemoglobin &lt; 120g/ml,0.6; tumor size≥80 mm,1.4; LDH level, 0.5; liver metastases, 1. C-statistic was 0⋅85, with extremely strong predictability (Table). The overall survival rate for patients with a higher score was significantly worse than lower cohort (Score: &lt; 0.6 vs. 1-2 vs. 2-4.1; OS: not reached vs. not reached vs. 8.3m; P &lt; 0⋅001). Conclusions: The nomogram facilitates personalized assessment of prognosis for Asian patients with advanced melanoma with PD-1 inhibitor. [Table: see text]