tbuckley/cabot-search huggingface dataset:
Impact of DNA damage repair alterations on real-world response to therapy in metastatic colorectal cancer.
Authors: Laura Miotke, Carter Norton, Christopher Duane Nevala-Plagemann, Vaia Florou, Zach Rubnitz, Ignacio Garrido-Laguna
Journal: Journal of Clinical Oncology (2024)

e15557 Background: Alterations in the DNA damage repair (DDR) pathway genes contribute to tumor development. These alterations can be exploited by cytotoxic chemotherapy regimens that induce DNA damage. Platinum chemotherapy agents have been shown to be particularly effective in breast and ovarian cancer patients with alterations in the DDR pathway. However, the clinical impact of DDR alterations in metastatic colorectal cancer (mCRC) is still poorly understood. In this study, we utilize a large national database to evaluate clinical outcomes in patients with mCRC and alterations in DDR pathway genes. Methods: We reviewed 5602 patients that received standard fluorouracil based first-line chemotherapy regimens for mCRC using the nationwide Flatiron Health EHR-derived de-identified database. Chemotherapy regimens were categorized as a platinum-based doublet (FOLFOX, CAPOX), irinotecan-based doublets (FOLFIRI), or triplet (FOLFOXIRI). Overall survival (OS) was summarized within groups via Kaplan-Meier survival estimates. OS was compared between groups in the context of univariable and multivariable Cox proportional hazards models controlling for age, gender, DDR status, stage at diagnosis, ECOG, RAS/RAF status, MMR status, albumin and CEA at diagnosis. OS was defined as the time in months between date of first line therapy initiation to death. Results: DDR gene alterations were indentified in 35.7% (2001) patients.The most frequent mutations were in ATM (13.3%) and BRCA2 (8.3%). There was no significant difference in OS based on DDR mutation status. Within DDR altered patients, there was no difference in OS between those who received a platinum-based doublet, irinotecan-based doublet or triplet first-line therapy. Time to next treatment or death (TTNTD) was significantly improved with an irinotecan-containing doublet regimen and triplet regimen compared to a platinum-based doublet in a multivariable model (HR 0.79, p = 0.001 and HR 0.68, p = 0.002, respectively). There was no difference in OS in DDR-mutated patients that received an irinotecan-based regimen in the first line followed by an oxaliplatin-based regimen in the second line or the reverse sequence. When evaluating the impact of commonly co-mutated genes on survival we observed a worse OS in patients with a KRAS mutation in addition to a DDR mutation (HR 1.19, p = 0.045). An APC mutation was associated with an improved OS in the entire cohort, regardless of DDR status (HR 0.76, p &lt; 0.001). Conclusions: In this real-world population, approximately one third of patients with mCRC harbored an alteration in a DDR pathway gene. In these patients, TTNTD was greater with irinotecan-containing first line therapies (doublet or triplet). However, OS was similar regardless of which first-line chemotherapy was used.
Characterization of <i>Von Hippel Lindau</i> gene variants by race.
Authors: Yusra F. Shao, Abdurahman Alloghbi, Seongho Kim, Bayan A Al-Share, Courtney Kokenakes, Elisabeth I. Heath
Journal: Journal of Clinical Oncology (2024)

e15158 Background: Autosomal dominant (AD) pathogenic/ likely pathogenic (P/LP) variants in the VHL gene cause Von Hippel Lindau syndrome, historically studied in White populations. We aimed to characterize VHL variants and disease phenotypes in both Non-White (NW) patients, which include Asian and African-American (AA), and in Non-Hispanic White (NHW) patients. Methods: Patients undergoing germline genetic testing (GGT) at Invitae Corporation from November 2014 to March 2022, carrying a P/LP AD variant in VHL gene were identified. Demographic and clinical data were obtained from Test requisition forms. Fisher's exact test and Wilcoxon rank-sum tests were performed for categorical and continuous variables, respectively, to compare groups. Results: The final analysis included 363 patients (NW=27%). Hemangioblastoma was predominant in all groups (NHW=13%, NW=27%, p=0.004). Breast cancer exclusively occurred in NHW patients (7%, p=0.019). NHW and NW patients had a higher family history of breast cancer (NHW=7%, NW=1%, p=0.046) and hemangioblastoma (NHW=3%, NW=8%, p=0.037), respectively. Distribution of VHL variants between NW and NHW patients varied significantly (p&lt;0.001, Indels p=0.009, substitution variants p&lt;0.001). Deletion exon 2 was predominant in all groups (NHW=15%, NW=35%) P.Leu188Val was exclusive to NHW patients (26%)while p.Arg167Trp (NHW=6%, NW=11%) and p.Arg167Gln (NHW=2%, NW=10%) were more common in NW patients. Several unique variants in AA and Hispanic patients were seen. Conclusions: This study reveals differences in P/LP VHL variant distribution and disease phenotype between NHW and NW races. Ethnicity-specific characterization uncovers unique variants in AA and Hispanic patients. This dataset informs future research on VHL disease and treatment in diverse populations.
Outcomes of patients with peritoneal carcinomatosis treated with HIPEC and chemotherapy or HIPEC alone: A single center community experience.
Authors: Benjamin Michael Huber
Journal: Journal of Clinical Oncology (2024)

e15578 Background: Peritoneal carcinomatosis is a common presentation of intraperitoneal malignancies. The optimal management of peritoneal carcinomatosis is currently unknown but can contain a combination of HIPEC and chemotherapy. Optimal timing and order of these interventions is controversial. HIPEC surgery alone can provide a cure rate of approximately 16% with macroscopically complete resection. The PRODIGE 7 trial demonstrated no difference in overall survival between HIPEC plus cytoreduction versus cytoreduction alone with six months of systemic chemotherapy. Which patients should receive HIPEC, chemotherapy and HIPEC or chemotherapy alone remains unknown. Methods: This is a single center, retrospective chart review assessing all patients age 18 and above who received HIPEC surgery with and without the administration of chemotherapy at Ascension Saint John Hospital. Results: We found that there was no significant difference in overall survival and progression free survival between the HIPEC and HIPEC with chemotherapy group with a OS of 57.2 months and 52.5 months; and PFS of 33.6 and 34.4 months respectively. We found that patients with a PCI score between 0 and 13, overall survival favored the HIPEC alone group versus the HIPEC with chemotherapy with a p value of 0.043. There was no difference in progression free survival and overall survival in all other groups when stratified by PCI. When stratified by disease subtype, we no differences between PFS and OS for both appendiceal and colon cancer. Conclusions: The primary objective of this study was to investigate the difference in overall survival and progression free survival among patients with peritoneal carcinomatosis when treated with either HIPEC with systemic chemotherapy versus HIPEC alone. This analysis among 100 patients showed no statistically significant differences in OS or PFS for patients receiving a combination of HIPEC with systemic chemotherapy versus HIPEC alone. The only exception to this was with respect to OS in patients with a PCI score between 0-13. In this group, 0 patients in the HIPEC along group experienced disease progression where 5 progressed in the HIPEC and chemotherapy group. Our data suggests that HIPEC alone may be a reasonable treatment approach for patients with a low PCI score. Important conclusions can be drawn from the data when compared to historical trials. The PROTEGE 7 study found that the median overall survival was approximately 41.7 months for the HIPEC and cytoreductive surgery group and 41.2 months versus cytoreductive surgery alone. The overall survival for the HIPEC alone group was 57.2 months and 52.5 months for the HIPEC plus chemotherapy group. This data suggests that the combination of HIPEC and chemotherapy is a reasonable approach to patients with peritoneal carcinomatosis.
Combined amphiregulin and epiregulin expression as a prognostic and predictive biomarker of panitumumab (Pmab), fluorouracil, and folinic acid (FU/FA) or FU/FA maintenance therapy following Pmab+FOLFOX induction in <i>RAS</i> wildtype metastatic colorectal cancer (mCRC): PANAMA trial (AIO-KRK-0212).
Authors: Arndt Stahler, Beeke Hoppe, Luisa Keilholz, Il-Kang Na, Meinolf Karthaus, Stefan Fruehauf, Ullrich Graeven, Ludwig Fischer Von Weikersthal, Stefan Kasper, Alexej Ballhausen, Greta Sommerhäuser, Annabel Helga Sophie Alig, Annika Kurreck, Swantje Held, Volker Heinemann, David Horst, Armin Jarosch, Sebastian Stintzing, Tanja Trarbach, Dominik Paul Modest
Journal: Journal of Clinical Oncology (2024)

3528 Background: mRNA expression of amphiregulin ( AREG) and epiregulin ( EREG) as ligands of the epidermal growth factor receptor (EGFR) were associated with response to anti-EGFR directed antibodies in metastatic colorectal cancer (mCRC). Their role for maintenance treatment remained unclear yet and was investigated in the PanaMa trial (panitumumab (Pmab) and fluorouracil/folinic acid (FU/FA) vs. FU/FA alone after Pmab+FOLFOX induction therapy in RAS wild-type mCRC). Methods: Gene expression was measured after mRNA isolation in 196 of 248 patients of the full analysis set. The analysis was conducted using a customized Nanostring PanCancer Progression Panel. AREG and EREG mRNA expression was dichotomized by median. High combined expression was defined as mRNA expression of AREG and EREGequal or above the median. Median progression-free (PFS) and overall survival (OS) since start of maintenance were estimated by Kaplan-Meier-method and Cox-regression, using the log rank test. Objective response rates (ORR) of maintenance therapy were compared by Fisher’s exact test. Treatment interaction was tested by Cox regression. Results: In 196 patients with available mRNA expression data, high AREG, EREG and combined AREG / EREG expression were observed in 103 (52.6%), 97 (49.5%) and 84 (42.9%), respectively. Regardless of treatment, high combined AREG / EREG expression was associated with prolonged PFS (7.7 vs. 5.8 months, HR 0.69 (95% CI 0.51 – 0.93), P=0.016), OS (30.1 vs. 24.4 months, HR 0.58 (95% CI 0.41 – 0.82), P=0.002) and increased ORR of maintenance treatment (39.3% vs. 28.6%, P=0.13), compared to low expression. Tumors with high combined AREG / EREG expression were associated with numerical longer PFS, OS and higher ORR when treated with Pmab+FU/FA maintenance (Table). Significant interaction of combined AREG / EREG expression with treatment was observed in terms of PFS ( P=0.003) and OS ( P=0.016). Conclusions: Combined AREG and EREG mRNA expression was confirmed as prognostic biomarker for mCRC patients receiving maintenance treatment. Efficacy of maintenance treatment might potentially be higher for Pmab+FUFA maintenance in mCRC with high combined AREG / EREG expression in the PanaMa trial. [Table: see text]
The impact of treatment approach on survival among patients with clinical stage T2N0 and T3N0 rectal cancer.
Authors: Tauseef Ur Rehman, Natalie Ceballos, Shenae Samuels, Pablo H. Ferraro, Christopher J. Gannon, Omar H. Llaguna
Journal: Journal of Clinical Oncology (2024)

e15637 Background: Treatment of early stage rectal cancer requires a multi-disciplinary approach and is often treated with curative intent surgery with use of total neoadjuvant treatment (TNT) or neoadjuvant chemoradiotherapy (nCRT) in select cases pre-operatively. In this study, we determine the various clinicopathologic factors associated with the use of these different approaches (Surgery upfront vs nCRT vs TNT) and their effect on patient survival. Methods: The National Cancer Database (NCDB) was queried for patients with clinical T2N0M0 and T3N0M0 rectal cancer between 2004-2019. Results: 36,869 patients were identified, of which about half had nCRT only while &lt; 15% had received TNT. Patients who underwent nCRT had the highest median OS compared to those who underwent surgery only (106.8 vs 126.5 months, p &lt; 0.001). The surgery upfront cohort had the highest proportion of patients who were seen at a facility with high/very high case volume per year quartiles (surgery: 52.5%, nCRT: 47.3%, and TNT: 48.3%, p &lt; 0.001). The highest median age was among the surgery cohort at 69 years followed by the nCRT cohort at 64 years and TNT cohort at 61 years (p &lt; 0.001). Amongst patients with a Charlson-Deyo co-morbidity score of 2 or more, the surgery upfront cohort had the highest proportion while the TNT cohort had the lowest (p &lt; 0.001). Low anterior resection (LAR) was the most common procedure among all three cohorts. A multivariate logistic regression model revealed that when compared to surgery only, the nCRT (Adjusted Odds Ratio (AOR) = 1.51, p &lt; 0.001) and TNT (AOR = 1.62, p &lt; 0.001) were both associated with an increased likelihood of 5-year long-term survival (LTS), with TNT having a stronger association. Among the various pre-operative characteristics, patients 70 years and older, patient with normal CEA and presence of LVI were less likely to have LTS with TNT as compared to surgery upfront. On the other hand, patients with clinical T3 stage who received TNT were much more likely to have improved LTS as compared to T2 stage (Relative Risk Ratio (RRR) 16.19, p &lt; 0.001). Conclusions: Results of our study show that patients with early stage T2N0 and T3N0 rectal cancer who underwent neoadjuvant treatment had an improved median OS compared to patients who received surgery upfront. Both nCRT and TNT were associated with an increased likelihood of long-term survival, with TNT having a stronger association particularly in the T3N0 cohort.
Circulating tumor DNA (ctDNA) kinetics in colorectal cancer (CRC) treated with curative intent in the VICTORI study with an ultrasensitive MRD assay.
Authors: Joao Paulo Solar Vasconcelos, Emma Titmuss, Fabio Navarro, Charles Abbott, Brendan Chia, James T. Topham, Gale Ladua, Tharani Krishnan, Daniela Hegebarth, Howard J Lim, Karamjit Gill, Sharlene Gill, Carl J. Brown, Amandeep (Anu) Ghuman, Adam Meneghetti, Daniel John Renouf, David F. Schaeffer, Richard Chen, Sean Michael Boyle, Jonathan M. Loree
Journal: Journal of Clinical Oncology (2024)

e15625 Background: Detection of molecular residual disease (MRD) with ctDNA is highly prognostic for recurrence in CRC. However, many cancers still recur without detectable ctDNA and increased lead time before clinical recurrence may create a window of opportunity to intervene. Here we apply an ultra-sensitive assay, NeXT Personal, to profile patients in the VICTORI study, a prospective cohort of patients with CRC managed with curative-intent treatment. Methods: To date, the first 33 patients with CRC have undergone panel creation. NeXT Personal was employed to construct personalized liquid biopsy panels for each patient with up to ~1,800 single nucleotide variants (SNV) identified via whole-genome sequencing. For each patient, plasma is collected before curative intervention (baseline), every 2 weeks for 2 months (MRD window), and every 3 months for up to 3 years (surveillance). VICTORI will enroll &gt; 175 patients and include a health economics analysis. Results: Of 33 patients enrolled to date, 25 (76%) are stage I-III and 8 are stage IV treated with curative interventions. 18 colon cancers and 15 rectal cancers are included. Pre-operative baseline sensitivity was 90.6% (29/32; 1 patient excluded as pCR at the time of baseline blood draw). Of the MRD- patients at baseline, 2 had prior neoadjuvant treatment and 1 was stage 1. Preliminary results (median 7.2 month follow-up; 5 recurrences) show 80% (4/5) of recurrences are MRD+ at the 4-week landmark and 50% (2/4; 1 missing sample) were MRD+ at the 2-week landmark. In 75% (3/4) stage II-III recurrences, the first MRD+ detection was in the ultra-low range of &lt; 100 PPM ( &lt; 0.01% tumor fraction). MRD detection at week 4 and 8 trended towards poorer recurrence-free survival (RFS) with similar separation of patients (log rank p = 0.062 and p = 0.011, respectively). Conclusions: Preliminary results from our prospective study demonstrate strong rates of ctDNA detection at week 4 landmark analysis, potentially due to detection of very low levels of ctDNA with an ultra-sensitive MRD assay. The majority of the first detections for MRD were in the ultra-low ctDNA range, indicating the importance of high sensitivity MRD testing. [Table: see text]
Outcomes of colorectal cancer hospitalization with and without coexisting nutritional anemia: A National Inpatient Sample (NIS) 2016 to 2019 database study.
Authors: Sagar Pandey, Madhav Changela, Kapilkumar Manvar, Dhruvanshu Patel, Sanket Basida, Yash Shah, Tejas Karawadia, Madhumati R. Kalavar
Journal: Journal of Clinical Oncology (2024)

e15648 Background: Colorectal carcinoma (CRC) is third most commonly diagnosed cancer in males and second in females. Implications of CRC with coexisting anemia and its outcomes of hospitalization have not been studied. We aim to evaluate the outcomes of CRC hospitalization with and without coexisting nutritional anemia. Methods: A total of 504,515 patients (male: 52.61%, female: 47.39%), aged ≥18 years, admitted from 2016 to 2019 with principal admission diagnosis of CRC were identified using International Classification of Disease 10 (ICD-10) coding for NIS database. Patients were stratified into those with and without nutritional anemia (16.19% vs 83.81%) which included iron, B12, folate deficiency and other nutritional anemia per ICD-10 coding. Mortality was the primary outcome of the study whereas length of stay (LOS), total treatment cost, acute kidney injury (AKI), pulmonary embolism (PE), deep vein thrombosis (DVT), colonoscopy, abdominal surgery and lower gastrointestinal (GI) bleeding were secondary outcomes. Multivariate regression model was used to estimate the outcomes of CRC hospitalization with and without coexisting nutritional anemia after adjusting for confounders like age, sex, race, insurance provider, co-morbidities, median income, hospital region, location, etc. Results: Mean age of patients admitted with CRC with and without anemia was 69.06 and 65.77 years respectively. Among two groups, mortality was significantly lower among patients with nutritional anemia (2.05 % vs 2.64 %). Lower GI bleeding (12.24% vs 4.77%) and colonoscopy during inpatient stay (43.97% vs 23.05%) were significantly higher among CRC cohort with nutritional anemia. Similarly, LOS, cost of inpatient hospitalization, AKI, PE and DVT were also significantly higher among anemia cohort. However, the need for abdominal surgery was significantly higher among CRC patients without nutritional anemia. Table 1 summarizes the results of multivariate regression analysis. Conclusions: Nutritional anemia in CRC patients is associated with longer length of stay, increased cost, higher risk of developing venous thrombosis along with lower GI bleed and colonoscopy. Therefore, it should be corrected to optimize outcomes among CRC patients. [Table: see text]
Development of HLB3-002 (recombinant human PH20 stand-alone) and its applicability as an anticancer diffusion agent.
Authors: Heeyoun Kim, Juyoung Byun
Journal: Journal of Clinical Oncology (2024)

e15195 Background: HLB3-002 is a standalone of Halozyme's rHuPH20 (Original) and has the same amino acid sequence. HLB3-002 is being developed as a drug diffusion agent that decomposes subcutaneous hyaluronan, allowing substances such as anticancer drugs to be administered subcutaneously. This study was conducted to compare the in vivo efficacy and PK of original and HLB3-002 to confirm equivalence and thereby prove its applicability as a drug diffusion agent. Methods: In the in vivo efficacy test, Trypan blue was mixed with each original and HLB3-002 and administered subcutaneously to confirm diffusion and reconstruction equivalence in the nude mouse. The PK test was conducted using Rituximab, prepared in the same formulation as Rituximab SC by adding HLB3-002. A single dose was administered subcutaneously to the nape of the rat, and 12 points were collected for 28 days. The PK samples were measured by ELISA. When the C max and AUC last ratios of Rituximab between 2 groups were within 80.00 to 125.00%, they were evaluated as biologically equivalent. Results: As a result of efficacy test, the diffusion area of HLB3-002 was 104.7% compared to the original, which was confirmed to have an equivalent diffusion efficacy. In the skin reconstruction test, it was confirmed that both original and HLB3-002 rebuilt the skin layer to a similar to the negative control after 48 hours. As a result of the PK, Compared to Rituximab SC, the C max of Rituximab+HLB3-002 was similar at 98.53% and AUC last at 95.50%. Conclusions: Through an in vivo efficacy and PK test, we confirmed an equivalent drug diffusion effect, confirming that HLB3-002 applicability as an anticancer drug diffusion agent.[Table: see text]
Application and evaluation of fecal SDC2 gene methylation in the diagnosis and treatment of colorectal cancer.
Authors: Rongjia Xie, Zhuqing Liu, Qing Xu
Journal: Journal of Clinical Oncology (2024)

e15541 Background: SDC2 gene encodes the transmembrane proteoglycan molecule Syndecan-2. Syndecan-2 protein affects the proliferation, migration and invasion of colorectal cancer cells by regulating cell adhesion, tissue differentiation and angiogenesis. The aim of this study is to verify the sensitivity and specificity of fecal SDC2 gene methylation in the detection of colorectal cancer, find the dominant population who can benefit from this detection, expand its clinical application scenarios, and explore its role in the evaluation of the efficacy and prognosis of patients with advanced colorectal cancer. Methods: A total of 72 patients diagnosed with colorectal cancer were included in the study. The methylation level of SDC2 gene in feces of patients was detected by fluorescence PCR. We evaluated sensitivity and specificity and assessed associations between fecal SDC2 methylation levels, fecal occult blood tests, characteristics of the lesions on colonoscopy, and clinical practice. The critical value of reaction solution A was 10.0, and the critical value of reaction solution B was 10.5. When the Ct value of any tube of reaction solution A or B was less than the critical value, it was judged as "positive". Results: Data from 72 patients were evaluated, with a sensitivity of 89.1% (41/46 95%CI 0.798 to 0.985) for patients with untreated colorectal cancer. The sensitivity of SDC2 methylation detection was 46.2% (12/26 95%CI 0.256-0.667) in patients with partial response or stable disease after palliative treatment. The difference in the detection rate of SDC2 methylation between the two groups was statistically significant (P &lt; 0.001). Among the 46 untreated patients with colorectal cancer, 32 patients with positive SDC2 gene methylation received radical surgery, and 30 of them (93.75%) turned to SDC2 gene methylation negative after surgery. Patients who achieved clinical benefit (CR+PR+SD) found reduced SDC2 gene methylation levels in the stool.There was no significant difference in the methylation level of SDC2 gene between colorectal cancer patients with different fecal occult blood test results (-, +, ++, +++) (P = 0.564)、different lesions (ascending colon, transverse colon , descending colon , sigmoid colon, and rectal) (P = 0.179)、different stages (stage I, II, III, IV) (P = 0.828)、different types (infiltrative, ulcerative, protruding) (P = 0.629), and different sizes of lesions (≤ 5cm, 6-9cm, ≥10cm) (P = 0.644). Conclusions: The high sensitivity of fecal SDC2 gene methylation in detecting untreated CRC patients may help make colonoscopy a screening method only for those at high risk of developing CRC. It may help to evaluate the efficacy of radical surgery, predict the recurrence of colorectal cancer and monitor the efficacy of palliative treatments for colorectal cancer. This work was supported by Shanghai Shenkang Project (No.SHDC2022CRT009).