tbuckley/cabot-search huggingface dataset:
The Gundersen Precision Oncology Cohort: A biospecimen resource for mutation characterization and target discovery.
Authors: Paraic Kenny, Peter Feiszt
Journal: Journal of Clinical Oncology (2024)

e15184 Background: The generation and widespread sharing of large somatic mutation datasets has revolutionized our understanding of genetic mechanisms driving cancer initiation and progression. For well-understood mutations, this has created the opportunity for individualized therapeutic intervention in a wide range of malignancies. Beyond these well-characterized mutations, there exists a wide range of alterations that remain poorly understood and which require some kind of functional genomics analysis to determine whether such patients are eligible for the targeted therapy used for more typical mutations in that gene, whether these alterations are passenger mutations that don’t affect throughput on the associated signaling pathway, or reflect another more nuanced phenomenon. Whether using ectopic overexpression in cell lines or generation of genetically modified mice, addressing this problem at scale using functional genomics approaches is challenging. A key limitation is the absence of the original tissue context in which that variant co-evolved with other genetic alterations as well as data on the clinical response of the patient to successive lines of therapy. This can be addressed, in part, by the banking of tissue from patient cohorts who have had comprehensive genomic profiling as part of their routine clinical care. For this purpose, we have established the Gundersen Precision Oncology Cohort. Methods: The Gundersen Precision Oncology Cohort is a retrospective collection of tissue specimens, NGS reports and associated clinical data from deceased patients who received cancer care at the Gundersen Health System. The cohort is updated twice per year and banked tissue specimens are available for collaborative research studies. Results: At November 20, 2023 there were data from 780 patients in the cohort, with specimens tested between 2015 and 2023. 54 tumor types were represented, of which lung (n = 196), colorectal (n = 79), pancreas (n = 65), esophageal (n = 58) and breast (n = 46) were most common. The most common diagnostic companies were STRATA Oncology (n = 463) and Tempus (n = 248). Most patients had testing at a single timepoint, but longitudinal testing is available for 13 patients. We present data from some of the studied subgroups, including atypical point mutations in BRAF as well as fusions affecting BRAF and ROS1. Conclusions: This cohort, available for collaborative studies via the Gundersen Cancer Biobank, illustrates the value of banking well-annotated biospecimens to address outstanding questions in oncology.
Neoadjuvant chemotherapy versus surgery plus adjuvant chemotherapy for locally advanced colon cancer: A meta-analysis of randomized controlled trials.
Authors: Barbara Klyslie Kato, Bernardo Fontel Pompeu, Lucas Monteiro Delgado, Fernanda Bellotti Formiga, Daniele Evaristo Vieira Alves
Journal: Journal of Clinical Oncology (2024)

e15631 Background: The primary treatment for colon tumors is surgical resection, but the use of neoadjuvant chemotherapy (NAC) in managing locally advanced cases remains a subject of ongoing debate. We conducted a thorough meta-analysis, including randomized clinical trials (RCTs), to assess the oncological safety of neoadjuvant chemotherapy (NAC) in colorectal tumor patients. Methods: We systematically searched in PubMed, Scopus, Google Academic and Cochrane Library in January 2024 for studies that directly compared NAC versus surgery in patients with T3-4, N0-2, M0 colorectal cancer. We assessed overall survival (OS) and disease-free survival (DFS). We calculated odds ratios (ORs) and hazard ratios (HRs) using generic inverse variance in Review Manger 5.4. Heterogeneity was assessed using I² statistics. Results: We included seven RCTs, involving 4,391 patients. Among them, 53.5% underwent NAC, with a median age of 61.41 years and an average follow-up of 62.35 months. The comprehensive analysis revealed no statistically significant differences in 3-year OS (OR: 1.20, 95% CI: 0.91 to 1.59, p = 0.20), more than 2 years DFS (OR: 0.88, 95% CI: 0.37 to 2.13, p = 0.78) and five-year DFS (OR: 1.09, 95% CI: 0.83 to 1.43, p = 0.55). Employing a time-to-effect modeling approach, there was no significant difference in OS (HR: 1.04, 95% CI: 0.63 to 1.70, p = 0.88) or DFS (HR: 0.86, 95% CI: 0.7 to 1.06, p = 0.16); (Table 1). Conclusions: Our systematic review and meta-analysis of seven RCTs showed that neoadjuvant chemotherapy compared with surgery followed by adjuvant chemotherapy had similar overall survival and disease-free-survival in patients with locally advanced colon cancer. [Table: see text]
Single-center retrospective analysis of second-line treatment with regorafenib in patients with advanced colorectal cancer among the COVID-19 pandemic.
Authors: Yu Xiao, Zhentao Liu, Baoshan Cao
Journal: Journal of Clinical Oncology (2024)

e15552 Background: Regorafenib targets multiple tyrosine kinases that has been approved for the third-line treatment in metastatic colorectal cancer (mCRC) patients in China. Here, We retrospectively analyzed the efficacy and safety of regorafenib alone or combined with chemotherapy/immunotherapy in the second-line treatment for those who cannot visit hospital for their chemotherapies because of the COVID-19 pandemic. Methods: Individual patient data from Peking University Third Hospital were analyzed retrospectively from January 2020 to September 2023. The primary endpoint was progression-free survival (PFS), and secondary endpoints were overall survival (OS) and safety. Results: The median age of 31 patients was 65 years, the median PFS was 6 months (1–21 months), and the median OS was 20 months (3–38 months). PFS tended to be prolonged with regorafenib plus capecitabine or immunotherapy in 12 subjects versus regorafenib alone in 19 subjects (8 months vs. 4 months, P = 0.306), with no statistical difference, and so did OS (27 months vs. 15 months, P = 0.899).The analysis of PFS (2.5 months vs. 7 months vs. 4 months, P = 0.164) and OS (13 months vs. 28 months vs. 20 months, p = 0.417) in patients with liver, lung, or abdominal/peritoneal metastases at the initiation of treatment demonstrated poor survival prognosis in patients with liver metastasis. Multivariate analysis showed that regorafenib combined with capecitabine or immunotherapy (wald = 5.766, p = 0.016) and non-liver metastasis (wald = 4.223, p = 0.040) were independent prognostic factors for PFS in the second-line treatment. Adverse drug reactions (ADRs) mainly included hand-foot skin reactions (HFSRs), fatigue, hypertension, and proteinuria, due to which 3 subjects discontinued the treatment. The incidence of Grade 3/4 ADRs was 19.3%, 16.9%, 12.9%, and 9.6%, respectively. Conclusions: Regorafenib alone or combined with chemotherapy/immunotherapy is safe and feasible in the second-line treatment for advanced colorectal cancer, and therefore further prospective studies can be conducted to explore combination therapies.
Three-year survival data from a phase 2 trial of neoadjuvant short-course radiotherapy followed by chemotherapy and camrelizumab in locally advanced rectal cancer.
Authors: Zhenyu Lin, Menglan Zhai, Peng Zhang, Kaixiong Tao, Tao Zhang
Journal: Journal of Clinical Oncology (2024)

e15611 Background: For locally advanced rectal cancer (LARC), short-course radiotherapy (SCRT) or long-course chemoradiotherapy combined with chemotherapy have been the established neoadjuvant treatment, but the optimal therapeutic modality is still under exploration. We previously reported the short-term results of neoadjuvant SCRT followed by chemotherapy and camrelizumab (a PD-1 inhibitor), encouragingly noting pathological complete response (pCR) in 48.1% of LARC patients (Lin Z et al. J Immunother Cancer 2021;9:e003554). Here, we report the further 3-year follow-up results. Methods: Adult patients with histologically confirmed T3-4N0M0 or T1-4N+M0 rectal adenocarcinoma were enrolled. Prior to surgery, eligible patients received 5×5 Gy SCRT, and after one week, they were treated with camrelizumab (200 mg, i.v., on day 1) plus CAPOX chemotherapy (oxaliplatin 130 mg/m 2 , i.v., on day 1 and capecitabine 1000 mg/m 2 , orally, bid, on days 1-14) in 21-day cycles for 2 cycles. Radical surgery was performed one week after the last neoadjuvant cycle. For this updated analysis, disease-free survival (DFS) and overall survival (OS) at 3 years are reported. Results: Thirty patients were enrolled and received SCRT, and all of these patients were included in this OS analysis. Among them, 27 patients received camrelizumab plus CAPOX chemotherapy, all of whom underwent surgery and were included in this DFS analysis. Of the 27 patients, 21 patients (77.8%) received at least one cycle of postoperative adjuvant chemotherapy with CAPOX regimen. With a median follow-up of 40.8 months (IQR 40.3-44.3), disease recurrence or death occurred in six (22.2%) patients. The median DFS and OS were both not reached, with the 3-year DFS and OS rates of 80.2% (95% CI 58.6-91.3) and 93.3% (95% CI 75.9-98.3), respectively. Subgroup analysis showed that patients with pCR, postoperative pathological node-negative status, PD-L1 combined positive score ≥ 1, and negative circumferential resection margin and negative extramural venous invasion by MRI at baseline had a tendency towards improved 3-year DFS and OS compared to those without these characteristics. No new or long-term safety signals were identified. Conclusions: With 3 years of extended follow-up, a favorable survival benefit was observed with neoadjuvant SCRT combined with subsequent CAPOX plus camrelizumab followed by delayed surgery in LARC patients. A randomized phase 3 trial (NCT04928807) is ongoing to confirm these results. Clinical trial information: NCT04231552 .
Updated results from ERAS-007 plus encorafenib and cetuximab (EC) in patients (pts) with EC-naïve metastatic BRAF V600E colorectal cancer (CRC) in the phase 1b/2 HERKULES-3 study.
Authors: Aparna Raj Parikh, E. Gabriela Chiorean, Chloe Evelyn Atreya, Lei Zheng, Scott Kopetz, Alexander I. Spira, David R. Spigel, Yue Cui, Ryan Osgood, Rebecca Tran, Shannon R. Morris, Susanna Varkey Ulahannan
Journal: Journal of Clinical Oncology (2024)

3517 Background: The RAS/MAPK pathway (including BRAF) is dysregulated in a broad range of cancers including CRC, resulting in downstream activation of ERK1/2. Patients (pts) with metastatic CRC with BRAF V600E mutation (BRAF V600E mCRC) have dramatically poorer survival rates than those with non-BRAF V600E mutated CRC, highlighting the need for novel therapies. The combination of a BRAF plus EGFR inhibitor is approved for the treatment of pts with BRAF V600E mCRC; however, objective response occurs in only 20% of pts. ERAS-007 is a novel, potent, and orally bioavailable inhibitor of ERK. ERAS-007 alone or in combination with encorafenib and cetuximab (EC) showed promising in vitro and in vivo activity in BRAF V600E CRC models, supporting investigation of the potential clinical benefit of ERAS-007 + EC in pts with BRAF V600E mCRC. Methods: HERKULES-3 is a Phase 1b/2 study to assess the safety, tolerability, pharmacokinetics (PK), and preliminary clinical activity of ERAS-007 combinations targeting the MAPK pathway in pts with advanced GI cancers. Within this study, we are currently evaluating the safety, tolerability, PK, and preliminary clinical activity of the combination of ERAS-007 + EC in pts with EC-naïve BRAF V600E CRC. Results: As of 30 November 2023, 19 (EC-naïve and EC-pretreated) pts have been dosed with ERAS-007 100 mg twice daily-once a week (BID-QW) in combination with EC (300 mg oral daily + 500 mg/m2 intravenous infusion every 2 weeks). The treatment-emergent AEs (TEAEs) occurring in ≥25% of pts were dermatitis acneiform (52.6%); nausea and fatigue (47.4% each); diarrhea (42.1%); constipation, headache, and hematuria (31.6% each); and vomiting, anemia, and infusion-related reaction (26.3% each). There were no Grade 4 TEAEs. One pt suffered a Grade 5 unrelated event of respiratory failure. There were no Grade 3 treatment-related AEs that occurred in more than 1 pt. There were no ERAS-007-related AEs that led to discontinuation of ERAS-007. Of the 19 pts, 11 were EC naïve and 10 of 11 were efficacy evaluable. In the EC naïve efficacy evaluable pts, the ORR was 40% with 3 of the 4 responses confirmed. The maximum duration of response is &gt; 15 months; updated data will be presented. Conclusions: ERAS-007 100 mg BID-QW in combination with EC was safe and well tolerated with preliminary evidence of promising clinical activity. These results support continued evaluation of this combination in EC naïve pts with BRAF V600E CRC. Clinical trial information: NCT05039177 .
Treatment of colon cancer using a novel approach comprising cytoreductive surgery in combination with hyperthermic intraperitoneal chemotherapy and intraoperative radiation therapy.
Authors: Marwan Alaswad, Tarek Arabi, Belal Nedal Sabbah, Abdullah Al Otry, Alwalid Hejazi, Aya Ismail, Heba Jaamour, Ziad Alhosainy, Samar Al Homoud, Ayman Azzam, Tarek Amin
Journal: Journal of Clinical Oncology (2024)

e15573 Background: Approximately 10% of colon cancer (CCa) develop peritoneal carcinomatosis. Studies have found that the administration of hyperthermic intraoperative chemotherapy (HIPEC) during cytoreductive surgery (CRS) can reduce the risk of recurrence and development of peritoneal carcinomatosis (PC). Additionally, intraoperative radiotherapy (IORT) has been shown to effectively treat and blunt neoplasm growth. However, no reports of the impact of concurrent HIPEC and IORT in CRS on CCa are available. Methods: We retrospectively reviewed the medical records of CCa patients with PC who received HIPEC and IORT during CRS. Demographics, treatment details, PC indexes (PCI), completeness of cytoreduction scores (CCS), and operative complications were recorded. Subsequently, overall survival (OS) was defined as the time period from surgery until death or loss of follow-up, and recurrence-free survival (RFS) was defined as the period from surgery until recurrence or loss of follow-up. Univariate hazard ratios (HR) were used to check for prognostic factors. Results: 17 CCa patients were included in our analysis. Patient characteristics are summarized in Table 1. The pT staging was T0 in 1 (5.9%), T3 in 6 (35.3%), T4a in 4 (23.5%), and T4b in 6 (35.3%). The pN staging was N0 8 (47.1%), N1a in 4 (23.5%), N1b in 2 (11.8%), N1c in 2 (11.8%), and N2b in 1 (5.9%). Finally, the pM staging was M0 in 8 (47.1%), M1a in 4 (23.5%), M1b in 2 (11.8%), and M1c in 3 (16.4%). PCI was ≤6 in 13 (76.5%) patients. The CCS was 0-1 in all, but two, patients. 1 patient had a positive resection margin. 8 (47.1%) received cisplatin with mitomycin C during HIPEC, followed by mitomycin alone (29.4%), reduced doses of cisplatin + mitomycin C (17.6%), and a reduced dose of mitomycin C alone (5.9%). Reduced dosage was due to old age in 3 and renal impairment in 1 patient. There were no intraoperative complications or HIPEC-related adverse effects. Two patients received two doses of IORT. 4 (23.5%) patients had postoperative complications, of which two complications were Clavein-Dindo grade 4a. Recurrence occurred in 8 (47.1%) patients, and 4 (23.5%) patients passed away. The median OS was not reached, and the RFS was 19 months. PCI &gt; 6 (HR: 12.6, 95% CI: 1.6-256.8) and postoperative complication of grade 4 (HR: 8.6, 95% CI: 1-73) were associated with poor OS. Only PCI &gt; 6 was associated with poor RFS (HR: 10.4, 95% CI: 1.7-80.8). Conclusions: Postoperative complications in HIPEC+IORT during CRS are comparable to other accepted treatments for CCa. Large, double-arm studies are needed to compare the effectiveness of this treatment. [Table: see text]
Changes in US colorectal cancer mortality trends over the past 20 years.
Authors: Jia Yi Tan, Yong Hao Yeo, Wern Lynn Ng, Zhi Ven Fong, Justin T. Brady
Journal: Journal of Clinical Oncology (2024)

e15543 Background: In the last two decades, colorectal cancer (CRC) mortality has been decreasing in the United States (US). However, the mortality trends for the different subtypes of CRC, including different sides of colon, rectosigmoid, and rectal cancer remain unclear. Methods: We analyzed death certificate data from CDC WONDER from 1999 to 2020. We calculated age-adjusted mortality rates (AAMR) per 100,000 individuals of CRC and its different subtypes and examined the trends over time by estimating the average annual percent change (AAPC) using the Joinpoint Regression Program. Results: From 1999 to 2020, 1,166,099 deaths were attributed to CRC, of which 957,182 deaths (82.08%) were due to colon cancer, 148,862 deaths (12.77%) from rectal cancer, and 60,055 deaths (5.15%) from rectosigmoid cancer. The overall CRC rates decreased significantly from 26.42 (95% CI, 26.20-26.64) to 15.98 (95% CI, 15.84-16.12) per 100,000 individuals, with AAPC of -2.41 (95% CI, -2.55, -2.27). However, the AAMR of rectosigmoid cancer increased significantly from 0.82 (95% CI, 0.78 -0.86) to 1.08 (95% CI, 1.04-1.11) per 100,000 individuals and the AAMR of right-sided colon cancer increased from 0.57 (95% CI, 0.54-0.60) to 0.70 (95% CI, 0.67-0.73) per 100,000 individuals, with AAPC of +1.10 (95%, 0.21-2.00) and +2.06 (95% CI, 0.85 - 3.27) respectively. Men had higher AAMR of CRC than women (23.90 [95% CI, 23.84-23.96] vs. 17.03 [95% CI, 16.99-17.08] per 100,000 individuals). African Americans had the highest AAMR of CRC (26.93 [95% CI, 26.79-27.07]), followed by Whites (19.60 [95%, 19.56-19.64] per 100,000 individuals), American Indians (14.53 [95%, 14.15-14.92] per 100,000 individuals), and Asians (13.04 [95%, 12.89-13.19] per 100,000 individuals). The overall AAMR of CRC decreased for those aged ≥ 50 years but increased significantly from 1.02 to 1.58 per 100,000 individuals for those aged 15-49 years, with an AAPC of +0.75. The AAMR from CRC was the highest in the Midwest (21.04 [95% CI, 20.96-21.12] per 100,000 individuals), followed by the South (20.51 [95% CI, 20.44-20.57]), the Northeast (20.30 [95% CI, 20.22-20.38] per 100,000 individuals), and the West (18.03 [95% CI, 17.95-18.10] per 100,000 individuals). Rural populations had higher AAMR than urban populations (22.40 [95% CI, 22.30-22.49] vs. 19.60 [95%, 19.56-19.64] per 100,000 individuals). Conclusions: Although overall CRC mortality declined, there were rising trends in young-onset CRC, rectosigmoid cancer, and right-sided colon cancer. Disparities persist in terms of sex, race, geographic region, and urbanization level, emphasizing the need for targeted public health measures.
Transanal endoscopic microsurgery vs. radical surgery for mid-low rectal cancer in patients with clinical complete or near-complete response after neoadjuvant chemoradiotherapy.
Authors: Xiaoyuan Qiu, Jiaolin Zhou, Yi Xiao, Huizhong Qiu, Zhan Shen, Bin Wu, Wenzhuo Jia, Beizhan Niu, Fei Li, Hongwei Yao, Aiwen WU, Ke Hu, Huadan Xue, Weixun Zhou, Guole Lin
Journal: Journal of Clinical Oncology (2024)

e15616 Background: Following neoadjuvant chemoradiotherapy (nCRT), total mesorectal excision surgery used to be the standard therapy for locally advanced rectal cancer (LARC). However, the radical surgery is associated with high complication rates and impairs patients' quality of life, especially for non-sphincter preservation procedures. For the past two decades, nCRT followed by organ preservation strategies like watch-and-wait (W&amp;W) or local resection offers an alternative for patients being clinically evaluated with complete response or near complete response, however the oncological outcomes of these approaches require further exploration. Methods: We prospectively collected data on 80 patients with T3-4N0M0 or TanyN+M0 mid-low rectal cancer who achieved cCR or near-cCR after nCRT from May 2017 to September 2021 at 5 tertiary centers in China. Patients were divided into the TEM group (group A) or the radical surgery group (group B). Clinicopathological features, operative outcomes, oncological and functional results were analyzed. Results: A total of 76 cases were analyzed, with 38 in each group. Baseline characteristics were comparable between the two groups. Postoperative histology revealed 22 ypT0Nx(57.9%), 5 ypT1Nx(13.2%), 10 ypT2Nx (26.3%), 1 ypT3Nx(2.6%) in group A, and 18 ypT0N0 (47.4%), 5 ypT1N0 (13.2%), 11 ypT2-3N0 (28.9%), 1 ypT0N1 (2.6%), 3 ypT2-3N1 (7.9%) in group B. After a median follow-up of 61 months, 2 patients (5.26%) in group A experienced local recurrence, while none in group B. 8 patients (21.05%) in group A developed distant metastases compared to 5 (13.16%) in group B. There was no statistically significant difference between two groups in 5-year disease-free survival(P = 0.320), or 5-year overall survival (P = 0.425). Patients in group A had significantly faster postoperative recovery and a superior quality of life evaluated by the Wexner and LARS scores compared to group B. Conclusions: For cCR and near-cCR LARC patients after nCRT, organ preservation with TEM may serve as a staging method to evaluate local tumor persisrence. And it provides an alternative therapy for carefully selected patients who have needs to preserve sphincteric function or can’t tolerate radical resection, without significantly compensate long-term oncological outcomes. This strategy could relatively safely enable sphincteric function preservation for these patients with faster postoperative recovery and better quality of life. Clinical trial information: NCT03042000 .
Highly prognostic signature for stage II colon cancer from the TOSCA trial: The PROSIT study.
Authors: Alberto Puccini, Lorenzo Ferrando, Luca Mazzarella, Gianmaria Frige, Anna Maria Pessino, Alessandro Pastorino, Valentino Martelli, Anna Garuti, Veronica Di Antonio, Alberto Ballestrero, Valter Torri, Roberto Labianca, Matteo Fassan, Sara Lonardi, Gabriele Zoppoli, Alberto F. Sobrero
Journal: Journal of Clinical Oncology (2024)

3524 Background: The predictive and prognostic value of current biomarkers for guiding the treatment of stage II colon cancer (CC) is very limited. Here, we aimed to develop a prognostic transcriptional signature for high-risk stage II CC patients undergoing adjuvant treatment with either 3 or 6 months of FOLFOX4/CAPOX within the framework of the phase III TOSCA Italian trial. Methods: We conducted an observational retrospective study based on the TOSCA trial database, matching 62 patients with high-risk stage II CC who relapsed with 62 who did not. The matching criteria included the center of recruitment, pT stage, adjuvant treatment type and duration (3 or 6 months). Transcriptome sequencing was performed on material from centrally assessed FFPE blocks on an Illumina Novaseq 6000 instrument. Generated data were processed using the nf-core/rnaseq (v 3.14.0) pipeline, aligned to the human genome GRCh37/hg19, and analyzed for differential gene expression, requiring a minimum absolute log fold change of 1 and false discovery rate below 0.1. Enrichment analysis was performed using GSVA package with the z-score method. Results: Out of the 124 stage II CC cases considered for the present analysis, 60% received 3 months and 40% 6 months of adjuvant chemotherapy. The median age was 64 years (IQR 55.2-71.1), with 40% of the cancers being right-sided. Fifty-seven percent of the patients received FOLFOX, while the remaining were treated with XELOX. Of the 124 matched samples, 72 were of sufficient quality for RNA-seq.We identified a signature among the top 17 differentially expressed genes (absolute log fold-change &gt; 1, p-value &lt; 0.001, FDR &lt; 0.1, see Table). Patients exhibiting a lower prognostic signature (PROSIT-L) showed worse disease-free survival (DFS) compared to those with a high prognostic signature (PROSIT-H) (HR 3.5; 95% CI 1.53 – 7.9; p = 0.002), indicating its strong and independent prognostic value, regardless of the treatment received. Conclusions: The new transcriptomic signature may help in identifying stage II CC patients who are likely to relapse despite receiving adjuvant oxaliplatin-based treatment. [Table: see text]