tbuckley/cabot-search huggingface dataset:
Prophylactic para-aortic lymph node dissection after neoadjuvant chemotherapy for gastric cancer with bulky lymph node metastasis.
Authors: Furukawa Kenichiro, Yosuke Matsumoto, Wataru Soneda, Yusuke Koseki, Keiichi Fujiya, Yutaka Tanizawa, Etsuro Bando
Journal: Journal of Clinical Oncology (2024)

344 Background: Neoadjuvant chemotherapy (NAC) followed by D2 gastrectomy with para-aortic lymph node dissection (PAND) is the standard treatment for gastric cancer with extensive lymph node metastasis (ELM) in Japan. ELM includes bulky lymph node metastasis along the celiac artery and its branches (Bulky N2) and metastasis of para-aortic lymph nodes (PAN). However, the benefit of PAND for gastric cancer with Bulky N2 but without PAN involvement is unclear. The aim of this study was to evaluate the efficacy of prophylactic PAND after NAC for this subgroup of patients. Methods: We retrospectively reviewed 21 patients who underwent NAC followed by curative (R0) gastrectomy for Bulky N2 (+) but PAN (-) gastric cancer from 2008 to 2019. Bulky lymph node was defined as one lymph nodes ≥ 3cm or two adjacent lymph nodes ≥ 1.5cm each. PAN metastasis included no. 16a2/16b1 lymph node metastasis. PAND was defined as systematic lymph node dissection of PAN. Patients were divided into two groups: a D2+PAND group (11 patients) and a D2 group (10 patients). We compared the clinicopathological features, recurrence patterns, and survival outcomes between the two groups. Results: The most common NAC regimen was S-1+cisplatin (12 patients: 57%), and other regimens in D2+PAND group included docetaxel+S-1+cisplatin or oxaliplatin. The D2+PAND group had longer operation time (p=0.006), and tended toward more undifferentiated histological type (p=0.063), better pathological response (p=0.086), and higher rate of adjuvant chemotherapy (p=0.090) than the D2 group. The ypStage was similar between the two groups. Pathological PAN metastasis was detected in two patients (18%) in D2+PAND group. Recurrence occurred in seven (70%) patients in D2 group and three (27%) patients in D2+PAND group, and lymph node recurrence was observed in four (40%), and one (10%) patients, respectively. The D2+PAND group had significantly better overall survival, recurrence-free survival, and disease-specific survival than the D2 group (p=0.008, 0.008, and 0.020, respectively). Conclusions: Prophylactic PAND after NAC may reduce recurrence risk for locally advanced gastric cancer with Bulky N2 but without PAN involvement.
Association of candidate alterations with primary resistance to <i>KRAS G12D</i> targeting in colorectal cancer.
Authors: Khalid Jazieh, Jill Tsai, Mojun Zhu, Hao Xie
Journal: Journal of Clinical Oncology (2024)

170 Background: KRAS-mutant colorectal cancer (CRC) has a worse prognosis and greater resistance to therapy, attracting tremendous efforts to develop both allele-specific and pan-KRAS targeting agents including KRAS G12C and G12D inhibitors. CRC has demonstrated both primary and acquired resistance to KRAS G12C inhibitors, which can be better evaluated by circulating tumor DNA (ctDNA)-based next generation sequencing (NGS) methods without tissue sampling bias. Here, we utilized clinical ctDNA data to delineate the landscape of candidate alterations associated with primary resistance to KRAS G12D targeting in CRC. Methods: Samples from advanced CRC patients with Guardant360 data in 2021 were categorized into a KRAS G12D group and comparator groups of KRAS G12C and KRAS not detected (ND) according to KRAS mutation status. Demographics, MSI-H status, and blood tumor mutational burden (bTMB) were summarized and compared between groups using t-test for continuous variables and Fisher’s exact test for categorical variables. Co-occurrence patterns of alterations between KRAS and other genes were assessed. Primary resistance mutations were inferred by acquired resistance findings to KRAS G12C inhibitors reported by Awad et al. N Engl J Med. 2021 and Tanaka et al. Cancer Discov. 2021. Results: Among approximately 2500 samples, 16.8% had KRAS G12D, the most common KRAS mutation in CRC. The mean allele frequency of KRAS G12D (11.4%) is comparable to that of KRAS G12C (10.9%). Mean age (61.6 years), MSI-H frequency (3.8%), and mean bTMB (14.2 Mut/Mb) of KRAS G12D group is comparable to those of KRAS ND group. This contrasts with KRAS G12C with significantly lower mean age (60.2 years, p=0.01), lower MSI-H frequency (0.56%, p=0.03), and higher mean bTMB (16.3 Mut/Mb, p=0.02) compared to KRAS ND. Both KRAS G12D and G12C significantly co-occur with APC, PIK3CA, and SMAD4 alterations. FBXW7, AR, and KEAP1 alterations were unique co-occurrences to KRAS G12D, while KIT was unique to KRAS G12C. Candidate alterations associated with primary resistance in KRAS G12D CRC included simultaneously present mutations of KRAS Q61H (14.1%), G12V (6.4%), G12C (5.9%), G13D (3.6%), BRAF V600E (2.7%) and others, amplification of MET (2%), MYC (1.6%), and KRAS (1.4%), and FGFR3-TACC3 translocation (Table). Conclusions: KRAS G12D is associated with unique co-occurring molecular alterations compared to KRAS G12C in CRC. ctDNA-based NGS platforms can survey candidate alterations associated with primary resistance to KRAS G12D targeting in CRC. Further validation in preclinical models is needed. [Table: see text]
Characterizing differential efficacy and phenotypic response to proteasome and survivin inhibitors in colorectal cancers using a high throughput organoid assay.
Authors: Dana Zuaiter, Parmanand Ahirwar, Aman G Pokal, Zeelu H. Patel, Areesha A. Charania, Chelsea L. Crawford, Mary Kathryn Sewell-Loftin, Allan Tsung, Alex Kim, Karim I. Budhwani
Journal: Journal of Clinical Oncology (2024)

153 Background: Conventional monolayer cell cultures and xenograft models, while useful and economical in early drug discovery, cannot predict clinical efficacy. Further, preclinical screening assays that rely on differential metabolic activity between separate control and treated wells are incapable of capturing phenotypic response and could overstate efficacy for cells with high rates of proliferation. Consequently, over 95% of anticancer agents that show efficacy in preclinical studies, fail in clinical trials. Recently, patient-derived organoid (PDO) models have been utilized in developing platforms to predict clinical efficacy of preclinical formulations. If successful, such predictive ex vivo technologies could revolutionize cancer treatment by reducing cost and time-to-market for new, more effective therapeutics. Objective: Characterize a novel bioprinted organoid tumor (BOT) high-throughput screening ex vivo platform for drug response prediction (DRP) with known proteosome and survivn inhibitors in colorectal cancer. Methods: Bioink for 3D printing BOTs was prepared with HT-29 cells, an established NCI-60 human colorectal adenocarcinoma cell line with known sensitivity to proteosome and survivin inhibitors. Bioink was deposited layer-by-layer on multiple substrates, in various geometrical configurations, and cured in stages to allow cells and matrix to self-assemble with limited degrees of freedom. BOTs were screened 24h and 48h after printing with proteosome inhibitor Bortezomib and survivin inhibitor YM-155. BOTs were evaluated 48h and 72h after treatment using immunofluorescence live/dead assay. Morphological phenotypic changes resulting from treatment were also recorded. Results: Proteasome and survivin inhibitors have been reported to inhibit proliferation and induce cell death in colorectal cancer cells. A dose dependent response was observed for both agents in our novel BOT HTS thereby validating the platform. In addition, characteristic self-assembly of HT-29 cells was observed to be disrupted at effective doses and at certain concentrations below the effective dose. Traditional ATP assays are incapable of recording such phenotypic modulation. Further, a higher proliferation profile was observed in untreated BOTs suggesting that use of independent control wells in traditional assays could overstate efficacy of treatment. Conclusions: Functional high-throughput ex vivo DRP technologies have the potential to transform cancer treatment – from bench to bedside – along the drug discovery to market roadmap for much needed novel anticancer agents.
Real-world comparison of treatment outcomes between advanced esophagogastric junction adenocarcinoma and gastric adenocarcinoma.
Authors: Toru Kadono, Toshiharu Hirose, Hidekazu Hirano, Hirokazu Shoji, Natsuko Tsuda Okita, Atsuo Takashima, Ken Kato
Journal: Journal of Clinical Oncology (2024)

267 Background: The characteristics of esophagogastric junction adenocarcinoma (EGJA) differ from those of gastric adenocarcinoma (GA). Although chemotherapy for advanced GA has been adapted for advanced EGJA, its efficacy remains unknown. This study aims to elucidate the effectiveness of chemotherapy for advanced EGJA in real-world practice. Methods: This retrospective study compared treatment outcomes between advanced GA and EGJA in patients with performance status (PS) 0 to 2 who received doublet or triplet chemotherapy, including platinum agents, as first-line treatment at our hospital between 2010 and 2020. Patients with non-curative resection factors limited to positive peritoneal cytology, or those who relapsed during adjuvant chemotherapy or within 6 months after its completion, were excluded. Results: Out of the total 825 patients, 765 had GA and 60 had EGJA. The baseline characteristics of the GA and EGJA groups were as follows, respectively: median age 65.0 and 59.5 years (p = 0.02); PS 0, 35.9% and 33.3%; PS 1, 57.5% and 65.0%; PS 2, 6.5% and 1.7% (p = 0.28); HER2 positive, 16.1% and 26.7% (p = 0.06); diffuse histology, 52.7% and 26.7% (p &lt; 0.01); lymph node metastasis, 74.0% and 93.3% (p &lt; 0.01); peritoneal metastasis, 66.4% and 25.0% (p &lt; 0.01); liver metastasis, 26.4% and 40.0% (p = 0.03); lung metastasis, 6.5% and 16.7% (p &lt; 0.01). The proportions of fluoropyrimidine, taxanes, and irinotecan in all treatment lines did not differ between the two groups (fluoropyrimidine, 99.7% vs. 100%; taxanes, 70.1% vs. 73.3%; irinotecan, 23.0% vs. 23.3%). However, the EGJA group used ramucirumab, trastuzumab, and immune checkpoint inhibitors (ICIs) significantly more frequently than the GA group (ramucirumab, 27.8% vs. 43.3%, p = 0.02; trastuzumab, 15.4% vs. 26.7%, p = 0.03; ICIs, 21.0% vs. 41.7%, p &lt; 0.01). Overall survival did not differ between the two groups (median, 14.8 months vs. 18.5 months, HR 0.80; 95% CI, 0.59-1.10, p = 0.17). Moreover, multivariate analysis revealed that EGJA and GA had a comparable prognosis (HR 1.23; 95% CI, 0.87-1.72, p = 0.24). HER2 positivity was a favorable prognostic factor in multivariate analysis, whereas diffuse histology, poor PS, lymph node metastasis, liver metastasis, and the presence of peritoneal metastasis were poor prognostic factors. There was no difference in time-to-treatment failure between the two groups for first-line (median, 6.1 vs. 4.9 months, HR 0.96; 95% CI, 0.73-1.28, p = 0.80), second-line (median, 2.9 vs. 3.5 months, HR 0.99; 95% CI, 0.73-1.34, p = 0.93), and third-line treatment (median, 1.9 vs. 2.7 months, HR 0.78; 95% CI, 0.53-1.13, p = 0.62). Conclusions: In real-world practice, the efficacy of chemotherapy for advanced EGJA was comparable to that for advanced GA.
Genomic characterization of unresectable/recurrent early-onset gastric cancer by comprehensive genomic profiling tests.
Authors: Kunihito Matsuguma, Hidekazu Hirano, Hiroyuki Fujii, Kouya Shiraishi, Hirokazu Shoji, Toshiharu Hirose, Natsuko Tsuda Okita, Atsuo Takashima, Takafumi Koyama, Ken Kato
Journal: Journal of Clinical Oncology (2024)

393 Background: The incidence of early-onset gastric cancer (EOGC: age ≤45 years) is showing an increasing trend. Although EOGC has unique clinicopathological features compared with late-onset gastric cancer (LOGC: age&gt;45 years), disparities in genetic alterations (GAs) between EOGC and LOGC are not fully understood in patients with unresectable/recurrent GC. We aim to investigate to elucidate unique GAs in unresectable/recurrent EOGC. Methods: We retrospectively reviewed data on patients with unresectable/recurrent GC who underwent comprehensive genomic profiling (CGP) tests and were registered as “Stomach adenocarcinoma (STAD)” cases in the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) in Japan from June 2019 to April 2023. CGP tests were conducted by NCC Oncopanel System (NOP) or FoundationOne CDx (F1). We examined somatic GAs, microsatellite instability (MSI) status, and tumor mutation burden (TMB) of GC. TMB-high was defined as ≥10 mutations/Mb. Actionable GAs were counted if they were classified as “pathogenic/oncogenic” or “likely pathogenic/likely oncogenic variants”. Druggable GAs are actionable GAs that can be treated with drugs approved for GC or other types of cancer or have shown efficacy in clinical trials for either GC or different types of cancer. Results: In total,112 patients with EOGC and 810 patients with LOGC were identified. In EOGC group, most common actionable GAs included TP53 (59.8%), ARID1A (17.0%), KRAS (15.2%), CDKN2A (11.6%), FGFR2 (11.6%), and CDH1 (9.8%). Compared to the LOGC group, the EOGC group exhibited a significantly higher frequency of actionable GAs in FGFR2(11.6% vs. 4.6%, P=0.0059), CDH1 (9.8% vs. 4.1%, P=0.015) and BAP1 (3.6% vs. 0.6%, P=0.016). On the other hand, the EOGC group showed a significantly lower frequency of actionable GAs in ERBB2(7.1% vs. 20.1%, P=0.0004), CCNE1 (4.5% vs. 19.0%, P=0.0001), and AURKA (0% vs. 7.9%, P=0.0003) compared with the LOGC group. In the EOGC group compared to the LOGC group, the proportions of MSI-high were 0.9% vs. 2.6% (P=0.345), and those of TMB-high were 4.5% vs. 11.6% (P=0.011). Excluding ERBB2 amplification, druggable GAs in the ECOG group included FGFR2 amplification (9.8%), MET amplification (4.5%), EGFR amplification (1.8%), KRAS G12C mutation (1.8%), and MDM2 amplification (0.9%). Conclusions: Among unresectable/recurrent GC population, EOCG has displayed distinct genetic profiles of GAs compared to LOGC. CGP tests may be useful in expanding treatment opportunities for patients with unresectable/recurrent EOGC.
Utilizing quantitative pathologic analysis of digitized images of rectal cancer (RC) to predict response to neoadjuvant therapy (NAT).
Authors: Daniel Walden, Cody Eslinger, Oluwadunni Eunice Emiloju, Michael H. Storandt, Catherine E. Hagen, Ashlyn Pfeiffer, Bassam Bassam Sonbol, Daniel H. Ahn, Tanios S. Bekaii-Saab, Andrew Ness, Christina Wu, Reetesh Pai, Fang-Shu Ou, Rish Pai, Joleen M. Hubbard
Journal: Journal of Clinical Oncology (2024)

200 Background: We developed and validated a quantitative segmentation algorithm (QuantCRC) to predict disease recurrence in stage I-III colorectal cancer patients (pts) based on the analysis of digitized hematoxylin and eosin (H+E) stained pathology slides. In this study, we aim to determine if QuantCRC analysis on pre-treated RC biopsies can predict pathological complete response (pCR) after NAT which include total neoadjuvant therapy (TNT), chemoradiation (CRT) and others. Methods: Stage II-IV RC pts treated with curative intent modalities between 2005-2023 at Mayo Clinic and University of Pittsburgh were evaluated. Eligible pts had pre and post-treatment tissue available for analysis. Clinical characteristics, treatment, and outcome data were extracted from the medical record. QuantCRC extracted 15 features: %tumor, %stroma, tumor:stroma ratio, %TB/PDC, %mucin, %necrosis, %high-grade, %signet ring cells, tumor-infiltrating lymphocytes (TILs) per cm 2 of a tumor, %immature stroma (tumor bed), %inflammatory stroma (tumor bed), %mature stroma (tumor bed), %immature (stromal region), %inflammatory (stromal region), and %mature (stromal region). The associations between the QuantCRC features and pCR were evaluated using Wilcoxon rank-sum tests and logistic regression models while adjusting for primary tumor location and NAT. Results: The identified 288 pts had the following demographics: median age 60, 59% male, 52% distal tumor, 42% TNT. Pts who achieved pCR had smaller pre-treatment tumors (p=0.03), higher TILS, and lower %immature (stroma) (Table 1). After multivariable adjustment, higher TILS and lower %immature (stroma) remain to be significantly associated with a higher likelihood of pCR. A higher %mature (stroma) and %mature stroma (tumor bed) were also identified, in multivariable models, to be associated with a higher rate of pCR. NAT protocol and tumor location (proximal vs. distal) were not associated with pCR. Conclusions: The ability to integrate pathological features with AI may allow for personalized treatment. Using this technology, we recognize that patients who harbor a more mature stromal archetype and inflammatory tumor predisposition, are more likely to achieve pCR to conventional NAT. These pathological features are not currently incorporated into risk stratification in RC. Additional validation and integration into current risk stratification methods is warranted. [Table: see text]
The power of glycobiology: Precision of polyp detection using glycoproteomic biomarkers.
Authors: Dharini Chandrasekar, Nik Sheng Ding, Michael B. Wallace, Daniel Norez, Christina Guerrier, Prasanna Ramachandran, Tomislav Caval, Khushbu Desai, Gege Xu, Daniel Serie, Daniel Hommes
Journal: Journal of Clinical Oncology (2024)

22 Background: Glycosylation plays a pivotal role in host immune response during cancer development. Recently, we have reported specific changes in blood-based glycoforms for the early detection of advanced adenomas (AAs) and colorectal cancer (CRC). This study aims to identify glycoproteomic biomarkers associated with various polyp types, as glycosylation abnormalities are linked to neoplastic transformation, and CRC risk varies by polyp histology. Methods: Samples from an observational study (NCT05445570) were used to identify three distinct histologic polyp groups: adenomatous (AP), hyperplastic (HP), or serrated (SP). Combining liquid-chromatography/mass-spectrometry and artificial-intelligence powered data processing, our glycoproteomic profiling platform assessed glycopeptide (GP) and non-glycosylated peptide quantification transitions from the serum samples. We used multi-nominal response logit models to examine the relationship between polyp types and biomarkers. An a priori biomarker panel was interjected as exposures in the model. Each marker is assessed independently for inclusion into our final model. The final model utilized biomarkers found to have a significant association with the presence of AP, SP, or HPs along with age, sex, and BMI. Results: We identified 1,035 subjects with distinct polyp histologies and 1,300 polyp-free controls. We found a significant increase in relative risk (RR) for polyp presence in patients who were: &gt;60 years (AP RR 1.40), male (AP RR 1.74), or had a BMI&gt; 25. From the GP biomarker panel, 15 GPs were associated with risk of polyp presence; however, only 7 GP markers were significantly associated after adjusting for age, sex, and BMI. Two biomarkers were found to have a protective effect for the risk of an adenomatous polyp (RR 0.37; RR 0.39). Three biomarkers increased the risk of an adenomatous polyp (RR 1.31; RR 1.42; RR 1.98). One biomarker was found to increase the risk of a hyperplastic polyp (RR 1.42). Two biomarkers were found to increase the risk of serrated polyps (RR 1.67; RR 2.08) and one biomarker was found to decrease the risk of serrated polyps (RR 0.77). Conclusions: This is a novel exploratory study using GP biomarkers as it relates to risk of polyp presence by distinct histology. The use of these biomarkers allows us to harness the power of glycobiology in the liquid biopsy domain for AAs/CRC detection. The exact function of these GP markers during the development of different polyp types needs to be further explored through future studies.
Pathologic complete response among patients with esophageal cancer receiving neoadjuvant chemotherapy or chemoradiation: A meta-analysis.
Authors: Charles Gaber, Jyotirmoy Sarker, Abdullah Abdelaziz, Ebere Okpara, Todd Lee, Samuel J. Klempner, Ryan David Nipp
Journal: Journal of Clinical Oncology (2024)

305 Background: Although neoadjuvant therapy improves overall survival in esophageal cancers, the benefit is largely confined to those with the greatest pathologic response. Current estimates of pathologic complete response (pCR) rates come from individual studies and lack precision. With this study, we sought to estimate summary pCR rates in patients with non-metastatic esophageal cancer who received either neoadjuvant chemotherapy or chemoradiation by conducting a systematic review and meta-analysis of clinical trials. Methods: Studies were identified from the Medline, EMBASE, and CENTRAL database searches. Eligible studies were published in English from 1992-2022 and consisted of clinical trials that focused on incident non-metastatic esophageal cancer or cancer of the gastroesophageal junction. Trials were required to contain at least one arm of patients receiving neoadjuvant chemotherapy (including perioperative) or neoadjuvant chemoradiation (including treatment with induction chemotherapy). Eligible studies had to report pCR in at least 20 patients who underwent neoadjuvant therapy and surgery. Pooled pCR prevalence was determined using the Freeman-Tukey double arcsine transformation and a random effects model. Results: Among 6,575 records first identified, we included 75 studies with 5,988 patients in the meta-analysis. Of the included studies, 38 (51%) were single arm trials, 35 (47%) were randomized trials, and 2 (3%) were non-randomized trials of multiple treatments. Geographically, 28 (37%), 24 (32%), 21 (28%), and 2 (3%) of the included trials were performed in Asia, Europe, North America, and Australia, respectively. Across 91 trial arms that delivered either neoadjuvant chemotherapy or chemoradiation, platinum and fluorouracil-based regimens were the most common (48.4%), followed by platinum and taxane-based regimens (26.4%), regimens that contained platinum-based agents, fluorouracil, and a taxane (13.2%), and other regimens (12.1%). The pooled prevalence of pCR after neoadjuvant chemotherapy in squamous cell carcinomas was 9% (95% CI: 6% – 14%) across 16 studies, ranging from 0%-32%. The pooled prevalence of pCR after neoadjuvant chemoradiation in squamous cell carcinomas was 32% (95% CI: 26% – 39%) across 21 studies, ranging from 8% to 66%. For adenocarcinomas, the pooled prevalence of pCR was 2% (95% CI: 0% – 7%) after neoadjuvant chemotherapy, across 3 studies, and 22% (17% - 27%) after neoadjuvant chemoradiation across 11 studies. Conclusions: In this meta-analysis, we found that under one-third of patients with non-metastatic esophageal cancer who receive neoadjuvant chemo(radiation) experience pCR. As pCR represents an increasingly utilized as an endpoint in neoadjuvant trials, these estimates of pooled pCR rates may serve as an important benchmark for future trial design.