tbuckley/cabot-search huggingface dataset:
Genomic introgression through interspecific hybridization counteracts genetic bottleneck during soybean domestication
Authors: Xutong Wang, Liyang Chen, Jianxin Ma
Journal: Genome biology (2019)

Evidence of introgression, the transfer of genetic material, between crops and their wild relatives through spontaneous hybridization and subsequent backcrossing has been documented; however, the evolutionary patterns and consequences of introgression and its influence on the processes of crop domestication and varietal diversification are poorly understood.We investigate the genomic landscape and evolution of putative crop-wild-relative introgression by analyzing the nuclear and chloroplast genomes from a panel of wild (Glycine soja) and domesticated (Glycine max) soybeans. Our data suggest that naturally occurring introgression between wild and domesticated soybeans was widespread and that introgressed variation in both wild and domesticated soybeans was selected against throughout the genomes and preferentially removed from the genomic regions underlying selective sweeps and domestication quantitative trait locus (QTL). In both taxa, putative introgression was preferentially retained in recombination-repressed pericentromeric regions that exhibit lower gene densities, reflecting potential roles of recombination in purging introgression. Despite extensive removal of introgressed variation by recurrent selection for domestication-related QTL and associated genomic regions, spontaneous interspecific hybridization during soybean domestication appear to have contributed to a rapid varietal diversification with high levels of genetic diversity and asymmetric evolution between the nuclear and chloroplast genomes.This work reveals the evolutionary forces, patterns, and consequences of putative genomic introgression between crops and their wild relatives, and the effects of introgression on the processes of crop domestication and varietal diversification. We envision that interspecific introgression serves as an important mechanism for counteracting the reduction of genetic diversity in domesticated crops, particularly the ones under single domestication.
Decreasing BMI/weight immediately prior to starting anti-PD-1/PDL-1 monoclonal antibodies for treatment for stage IV non-small cell lung cancer is associated with shorter progression-free survival.
Authors: Revathi Kollipara, Ibtihaj Fughhi, Marta Batus, Sanjib Basu, Jeffrey Allen Borgia, Philip D. Bonomi, Mary J. Fidler
Journal: Journal of Clinical Oncology (2019)

e20710 Background: Currently, prognostic markers associated with immunotherapy treatment outcomes in patients with metastatic NSCLC include PDL-1 expression, tumor mutational burden (TBM), and neutrophil to lymphocyte ratio (NLR). In this study we examine the influence of pretreatment changes in weight, BMI, and NLR in 237 patients treated with anti-PD-1/PDL-1 therapy (ICI) at our institution. Methods: This was a retrospective analysis of previously-treated stage IV NSCLC patients who received ICI. Pretreatment (≥ 6 weeks before starting therapy) values of weight, BMI, and NLR were compared to baseline values and NLR was analyzed as continuum and according to standard cutoffs of 3.5 and 5. The same variables were correlated with progression-free survival (PFS) and overall survival (OS) using the Log-Rank test. Results: 237 patients were analyzed: 45% were male, 73% were Caucasian, 72% were former smokers, and 25% were age ≥ 75 years. 148 patients had pretreatment NLR values. Of these, 32% had a ratio &lt; 3.5 and 54% had ratio &lt; 5. 34% had increased NLR at baseline, the majority of which (48/77) had a &gt; 5% increase. 187 patients had pretreatment weight and BMI. Of these, 14% had a pretreatment BMI &lt; 20. 71% had a negative change in BMI and 29% had a &gt; 5% decrease in BMI. 65% had a negative change in weight and 26% had a &gt; 5% decrease in weight. BMI decrease greater than 5% (p = 0.0039), negative weight change (p = 0.0371), and pretreatment NLR &gt; 5 (p = 0.0136) were associated with shorter PFS. Change in NLR trended towards decreased PFS but was not statistically significant (p = 0.07) though only 77 of 237 patients had both values available. There was no statistical PFS difference between patients less than or ≥ 75 years old. Conclusions: The results suggest that decrease in pretreatment BMI and weight along with high baseline NLR are associated with significantly shorter PFS in NSCLC treated with anti-PD-1/PDL-1 therapy. If confirmed, these observations raise the possibility that specific treatment which reverses cancer associated weight loss might enhance effectiveness of immunotherapy.
Comorbidity and racial differences in risk of mortality of men with breast cancer.
Authors: Carol Parise, Vincent Caggiano
Journal: Journal of Clinical Oncology (2019)

1554 Background: Black men with breast cancer have more concomitant disease and worse survival than white men. Less is known about concomitant disease and survival in Hispanic and Asian/Pacific Islander (API) men with breast cancer. The purpose of this study was to compare differences in survival and risk of mortality of white, black, Hispanic, and Asian/Pacific Islander (API) men with breast cancer with increasing comorbidity. Methods: We identified 1,497 cases of first primary male invasive breast cancer from the California Cancer Registry 2000-2015 with a documented Charlson Comorbidity Index (CCI). The CCI is a weighted index based on the presence of certain comorbid conditions following a cancer diagnosis and weighted by the severity of these conditions. A score of 0 indicates no significant comorbidity and scores of 2 or more are interpreted as a high comorbidity burden. Bivariate associations between race and AJCC stage, tumor grade, estrogen receptor (ER) status, human epidermal growth factor 2 (HER2), and socioeconomic status (SES) were compared using the χ 2 Test of Independence. Kaplan Meier Survival analysis was used to compare unadjusted survival among the races. Cox Regression was used to assess risk of mortality for each race when adjusted for factors that had a statistically significant (p &lt; 0.10) bivariate association with race/ethnicity. Analyses were conducted within each level of the CCI (0, 1, and 2 or more). Results: Among men with a CCI of 0 or 2, blacks had worse unadjusted survival than whites. There were no differences in survival for men with a CCI of 1. Stage, SES, ER, and type of surgery all had statistically significant bivariate associations with race/ethnicity. For men with a CCI of 0, Hispanics (HR = 0.367; 95% CI = 0.167, 0.801) and APIs (HR = 0.422; 95% CI = 0.189, 0.941) had a reduced risk of mortality when compared with whites. Black men had the same risk of mortality as white men. There were no differences in risk of mortality by race for men with a CCI of 1 or 2. Conclusions: Black men with breast cancer and no comorbidity have the same risk of mortality as white men while Hispanic and API men have lower risk of mortality. There are no racial disparities in adjusted risk of mortality in men with breast cancer with any concomitant disease.
Updated predictive analysis of the WHO-defined molecular subgroups of low-grade gliomas within the high-risk treatment arms of NRG Oncology/RTOG 9802.
Authors: Erica Hlavin Bell, Minhee Won, Jessica L. Fleming, Aline P. Becker, Joseph P. McElroy, Edward G. Shaw, Minesh P. Mehta, David G. Brachman, Stanley Z. Gertler, Albert D. Murtha, Christopher J. Schultz, David B. Johnson, Nadia N. Laack, Grant Kirton Hunter, Ian R. Crocker, Arnab Chakravarti
Journal: Journal of Clinical Oncology (2019)

2002 Background: This study sought to update the predictive significance of the three WHO-defined molecular glioma subgroups ( IDHwt, IDHmt/noncodel, and IDHmt/codel) in the subset of specimens available for analysis in NRG Oncology/RTOG 9802, a phase III trial of high-risk low-grade gliomas (LGGs) treated with radiation (RT) with and without PCV after biopsy/surgical resection. Notably, this is the first phase III study to evaluate the predictive value of the WHO subgroups in LGGs using prospectively-collected, well-annotated long-term overall survival data, in a post-hoc analysis. Methods: IDH1/2 mutation status was determined by immunohistochemistry and/or next-generation sequencing. 1p/19q status was determined by Oncoscan and/or 450K methylation data. Treatment effects on overall survival (OS) and progression-free survival (PFS) by marker status were determined by the Cox proportional hazard model and tested using the log-rank test in a secondary and exploratory analysis. Results: Of all the randomized eligible high-risk G2 patients (N = 251) in NRG Oncology/RTOG 9802, 106(42%) patients had tissue available with sufficient quality DNA for profiling. Of these, 80(75%) were IDHmut; 43(41%) were IDHmut/non-co-deleted, 37(35%) were IDHmut/co-deleted, and 26(24%) were IDHwt. Upon univariate analyses, no significant difference in either PFS or OS was observed with the addition of PCV in the IDHwt subgroup. Both the IDHmut/non-co-deleted and IDHmut/co-deleted subgroups were significantly correlated with longer PFS (HR = 0.32; p = 0.003; HR = 0.13; p &lt; 0.001) and OS (HR = 0.38; p = 0.013; HR = 0.21; p = 0.029) in the RT plus PCV arm, respectively. Conclusions: Our analyses suggest that both IDHmut/non-co-deleted and IDHmut/co-deleted subgroups received benefit from treatment with PCV although sample size is limited and analyses are post-hoc. Our results also support the notion that IDHwt high-risk LGG patients do not benefit from the addition of PCV to RT. Funding: U10CA180868, U10CA180822, and U24CA196067. Also, R01CA108633, R01CA169368, RC2CA148190, U10CA180850-01, BTFC, OSU-CCC (all to AC). Clinical trial information: NCT00003375.
Add-on anti-vascularendothelial growth factor agents with the second-line chemotherapy in metastatic colorectal cancer: A meta-analysis of randomized trials.
Authors: Feng-Che Kuan, Liang-Tseng Kuo, Meng-Chiao Hsieh, Min-Chi Chen, Kuan-Der Lee
Journal: Journal of Clinical Oncology (2019)

e15059 Background: Whether the survival benefits of anti-VEGF agents in second-line treatment for metastatic colorectal cancer (mCRC) are confounded by clinical factors is unclear. Methods: We searched literatures from PubMed, Embase, Cochrane Library, and conference abstracts through February 2017. Results: Seven randomised controlled trials with total 4931 patients comparing add-on anti-VEGF agents and second-line chemotherapy with chemotherapy alone were included with extracted outcomes from published reports. The primary outcomes were progression-free survival (PFS) and overall survival (OS). Anti-VEGF agents improved PFS and OS (PFS: hazard ratio [HR], 0·78; 95% CI, 0·69–0·88; OS: HR, 0·86; 95% CI, 0·78–0·95) without significant subgroup differences in age(&lt; 65 or ≥65 years, p = 0·815), gender (p = 0·322), ECOG performance status (0 or ≥1, p = 0·514), number of metastases (1 or &gt; 1, p = 0·903), metastasis to the liver only (yes or no, p = 0·713), second-line chemotherapy regimen (oxaliplatin- or irinotecan-based, p = 0·509), and the previous use of bevacizumab (yes or no, p = 0·185). The funnel plots showed symmetrical patterns and the result of Egger’s test was insignificant (PFS, p = 0·220; OS, p = 0·361), indicating no apparent publication bias. Conclusions: For second-line treatment in mCRC, anti-VEGF agents play an important role in PFS and OS in all subgroups of patients.
Clinicopathologic characteristics of <i>NRG1</i> fusion-positive cancers: A single-institution study.
Authors: Alison M. Schram, Ryma Benayed, Romel Somwar, Natasha Rekhtman, Maria E. Arcila, Marc Ladanyi, David Michael Hyman, Alexander E. Drilon
Journal: Journal of Clinical Oncology (2019)

3129 Background: NRG1 rearrangements are oncogenic drivers across several tumor types. Chimeric proteins encoded by NRG1 fusions activate HER3, resulting in heterodimerization with HER2 and activation of downstream signaling. Preclinical and preliminary clinical data suggest that targeting HER3 may be an effective treatment strategy for patients with NRG1 fusion-positive tumors. We aimed to describe the clinical and genomic characteristics of patients identified at our institution with NRG1 fusions. Methods: We analyzed results from prospective targeted exome and/or RNA sequencing performed at Memorial Sloan Kettering between 2014-2018 involving &gt; 30,000 samples. NRG1 fusion-positive tumors were identified and these cases were manually reviewed. Results: NRG1 fusions were detected in 24 patients. Cancer types included lung (N = 9), pancreas (N = 7), breast (N = 5), prostate (N = 1), gallbladder (N = 1), diffuse large B-cell lymphoma (N = 1), and cancer of unknown primary (N = 1). 6/9 lung cancers had mucinous differentiation. The majority of patients were Caucasian (N = 17), half were female (N = 12) and ages ranged from 24-82 years-old. Targeted exome sequencing identified the fusion in 10/23 cases tested, including 2 not confirmed by RNA. The remaining 14 were detected using RNA. Fusion partners included CD74 (N = 6), SLC3A2 (N = 2), SDC4 (N = 2), ATP1B1 (N = 2), FOXA1 (N = 1), SLCA4 (N = 1), ROCK1 (N = 1), TNKS (N = 1), CCND1 (N = 1), PAK1 (N = 1), STAU3 (N = 1), RAD51 (N = 1), CD44 (N = 1), NCOR1 (N = 1), RBPMS (N = 1), and WHSC1L1 (N = 1). Pancreas cancers were KRAS wild-type and lung cancers had no co-occurring alterations in ALK, ROS1, EGFR, RET, MET, RAS, or RAF. All tumors were microsatellite stable. A durable response was achieved with anti-HER3 antibody therapy (GSK2849330) in a patient with a CD74- NRG1-rearranged invasive mucinous adenocarcinoma (previously reported). Four patients treated with an irreversible small molecule HER2 inhibitor (afatinib) did not respond to treatment, suggesting direct targeting of HER3 may be superior to HER2 inhibition in patients with NRG1 fusion-positive tumors. Conclusions: NRG1 fusions occur in several tumor types and may be amenable to targeting with HER3-directed therapy.
A novel algorithm to redefine blood-based tumor mutational burden for optimized prediction of clinical benefits from immunotherapy.
Authors: Zhijie Wang, Guoqiang Wang, Jianchun Duan, Jing Zhao, Zhengyi Zhao, Hua Bai, Shuhang Wang, Shangli Cai, Jie Wang
Journal: Journal of Clinical Oncology (2019)

e20514 Background: The previous reported predictive biomarker, blood-based tumor mutational burden (bTMB) can only predict progression-free survival (PFS) while failed to predict overall survival (OS) from atezolizumab over docetaxel, or to predict PFS or OS in the atezolizumab arm. Here we aimed to explore the underlying mechanism and develop an algorithm to redefine bTMB as a predictor of both PFS and OS from immunotherapy. Methods: Data from POPLAR (N = 211) and OAK (N = 642) trials was used for algorithm development in bTMB redefinition. The derived algorithm was validated in two independent NSCLC cohorts (cohort 1 N = 64; cohort 2 N = 184). Results: In POPLAR and OAK cohorts, bTMB-H was not associated with favorable OS (P = 0.68, HR 1.06; 95% CI, 0.81-1.38) from immunotherapy at the reported cut-point of 16, which was validated in our independent cohort 1 (P = 0.86, HR 0.39; 95% CI, 0.39-1.89). Further analysis showed that blood TMB was associated with maximum somatic allele frequency (Pearson r = 0.47 in POPLAR and OAK cohorts, Pearson r = 0.36 in the independent cohort 2), which was a negative prognostic factor and may impede the predictive value of bTMB. The bTMB was thus redefined (referred to as bTMB*) with mutations with allele frequency &gt; 5% filtered out, when the correlation between bTMB and MSAF became less correlated (Pearson r = 0.09 and 0.07, respectively). Both better PFS and OS benefits from atezolizumab over docetaxel was observed in the redefined bTMB-H group as tested in POPLAR (PFS HR = 0.41, 95% CI, 0.21-0.80; OS HR = 0.34, 95% CI, 0.16-0.71) and validated in OAK (PFS HR = 0.49, 95% CI, 0.33-0.71; OS HR = 0.47, 95% CI, 0.29-0.77) with the cut-point of 12, while there was no significant association in redefined bTMB-L group (P interaction = 0.01 and 0.04 for PFS and OS in POPALR, &lt; 0.001 and 0.06 for OAK PFS and OS in OAK). The results was further validated in our independent cohort 1 treated with anti-PD-1/PD-L1, where the redefined bTMB-H was also associated with favorable PFS compared with bTMB-L (Logrank P = 0.005, HR = 0.34, 95% CI, 0.26-0.75) and OS (Logrank P = 0.08, HR 0.35, 95% CI, 0.11-1.18). Conclusions: The allele frequency needs to be taken into consideration in the algorithm of bTMB. The redefined bTMB may serve as a predictor of both PFS and OS of immunotherapy.
Recurrence risk evaluation in stage IB gastric cancer with <i>TP53</i> codon 72 polymorphism.
Authors: Satoshi Nishizuka, Yukimi Ohmori, Takeshi Iwaya, Keisuke Koeda
Journal: Journal of Clinical Oncology (2019)

4044 Background: Post-operative adjuvant chemotherapy is not currently indicated for Stage IB gastric cancer. However, about 10% of these patients experience recurrence and metastasis. Our previous study on a panel of gastric cancer cell lines indicated that TP53 codon 72 polymorphisms may affect the degree of biological malignancy. Hence, we hypothesized that the TP53 codon 72 polymorphisms may have been associated with post-operative survival without adjuvant chemotherapy. In this study, we investigated the risk of recurrence after treatment of Stage IB gastric cancer patients carrying the TP53 codon 72 polymorphism and attempted to identify a subpopulation that should receive post-operative adjuvant chemotherapy. Methods: Among 658 gastric cancer patients who received gastrectomy with curative-intent, 130 Stage IB patients were enrolled in the present study. The TP53 codon 72 polymorphisms of formalin-fixed paraffin-embedded cancer tissue sections were assessed by direct sequencing using originally designed primers. Overall survival rate (OS) and relapse-free survival rate (RFS) were analyzed based on the status of TP53 codon 72 polymorphism "Arg/Arg", "Arg/Pro" and "Pro/Pro". The hazard ratio for each subgroup was compared by TP53 codon 72 polymorphism. All interaction p values were calculated using the likelihood test. Results: Of the 125 patients for whom polymorphism analysis results were available, the 5- and 10-year OS was 84.5% and 63.9%, respectively. The 5- and 10-year RFS was 82.2% and 64.3%, respectively. When the study cohort was divided into two groups according to polymorphism status (i.e., Arg/Arg and Arg/Pro vs. Pro/Pro), both the OS (hazard ratio [HR], 1.968; 95% confidence interval [CI], 0.770-7.430, p = 0.045) and RFS (HR, 1.976; 95% CI, 0.778-7.515, p = 0.033) of the Pro/Pro group across the entire observation period were significantly lower than those for the Arg/Arg and Arg/Pro group. The majority of recurrences in Pro/Pro occurred within three years from the operation. Conclusions: Among Stage IB gastric cancer patients that underwent gastrectomy with curative-intent, post-operative adjuvant chemotherapy may be considered immediately after surgery for patients carrying the TP53 codon 72 Pro/Pro polymorphism.
Analysis of symptoms and functional HRQoL scales in TAGS, a phase III trial of trifluridine/tipiracil (FTD/TPI) in metastatic gastric cancer (mGC).
Authors: Maria Alsina, Josep Tabernero, Kohei Shitara, Toshihiko Doi, Mikhail Dvorkin, Wasat Mansoor, Hendrik-Tobias Arkenau, Aliaksandr Prokharau, Michele Ghidini, Catia Faustino, Vera Gorbunova, Edvard Zhavrid, Kazuhiro Nishikawa, Takayuki Ando, Suayib Yalcin, Eric Van Cutsem, Donia Skanji, Catherine Leger, Javier Sabater, David H. Ilson
Journal: Journal of Clinical Oncology (2019)

4043 Background: The phase 3, randomized, double-blind, placebo-controlled study (TAGS) evaluated the efficacy and safety of FTD/TPI (35 mg/m² given orally twice a day on days 1–5 and 8–12 of a 28-day cycle) in mGC patients who had previously received≥2 prior regimens for advanced disease and demonstrated a clinically relevant and statistically significant benefit in OS and PFS with a predictable and manageable safety profile. HRQoL data and association between QoL and time to ECOG status deterioration (2 or more) are reported here. Methods: HRQoL was evaluated using EORTC QLQ-C30 and the gastric-specific module (QLQ-STO22) questionnaires at baseline and at every 4 weeks thereafter until treatment discontinuation. Prespecified key HRQoL were changes from baseline and time to deterioration. Changes ≥10 points were deemed clinically relevant. A time-dependent Cox-regression analysis was performed to evaluate the association of 10-point Global Health Status deterioration with worsening ECOG status. Results: Of 507 patients randomized, 332/337 (98.5%) of FTD/TPI and 164/170 (96.5%) of placebo had baseline QoL data. Overall compliance was 84% for both questionnaires. Demographic and disease were generally balanced between the two groups; QoL scores were also similar between groups. HRQoL was largely maintained during treatment in both arms for most items; mean changes from baseline remained under the 10-point threshold. Clinically relevant changes from baseline were observed only for pain relief at cycle 2 (favouring FTD/TPI); and improved role functioning at cycle 3 (favouring placebo). In a sensitivity analysis including death or progression as an event, FTD/TPI was associated with a positive trend suggesting a reduced risk of QoL deterioration across all scales compared to placebo (HRs ranged from 0.57 to 0.74. A 10-point Global Health Status deterioration was associated with a worsening ECOG status (HR, 95% CI, 1.5, 1.2 to 1.86). Conclusions: During the treatment period, HRQoL remained stable for most functional and symptom scales in both arms, suggesting that HRQoL is largely maintained with FTD/TPI. Treatment with FTD/TPI was associated with a positive trend toward a lower risk of QoL deterioration than placebo across all scales. Changes in QoL were informative for patients ‘expected ECOG status. Clinical trial information: NCT02500043.
Racial disparities in cancer survival: A trend analysis based on SEER data (1973-2010).
Authors: Seyed Navid Alavi, Chibuzo Eze, Poornima Pandellapalli
Journal: Journal of Clinical Oncology (2019)

1571 Background: African Americans have higher incidence of cancer and lower survival rates compared to other ethnicities. We studied the 5-year relative survival between black and white races for the most common cancers in the United States. Methods: Data was obtained from the SEER database, the largest population-based cancer database including 28% of US population. Data containing 5-year relative survival from the patients who were diagnosed from 1973 to 2010. We included data for cancers of colorectal, lung, prostate, breast and melanoma, the most common cancers in the United States. Results: For colorectal cancer average 5-year relative survival from 1973 to 2010 is 59.9% for whites and 51.5% for blacks. Same results for lung cancer are 14.6% for whites and 12.2% for blacks, for breast cancer is 84.5% for whites and 71.6% for blacks, for prostate cancer is 86.9% for whites and 80.5% for blacks, and for melanoma is 87.9% for whites and 66.4% for blacks. The average black to white 5-year relative survival ratio is 0.86, 0.84, 0.85, 0.92, and 0.76 for cancers of colorectal, lung, breast, prostate, and melanoma, respectively. This ratio has decreased from 0.89 to 0.86 and from 0.87 to 0.81 for colorectal and lung cancer, respectively and for cancers of breast, prostate and melanoma it has increased from 0.85 to 0.87, from 0.88 to 0.89, and from 0.73 to 0.80 respectively. Conclusions: Our analysis shows that for colorectal and lung cancer the survival rate difference between blacks and whites has increased over 4 decades but for cancers of breast, prostate and melanoma this ratio has decreased. Better understating of the factors contributing to racial differences in cancer survival has potential applicability in policymaking for a better and equal health care delivery.