bluuebunny/crossref_metadata_2025 huggingface dataset:
HCRN GI16-288: A phase II trial of perioperative CV301 vaccination in combination with nivolumab and systemic chemotherapy for resectable hepatic-limited metastatic colorectal cancer—Preliminary efficacy and correlative results.
Authors: Spencer Kristen Renee , Hochster Howard S. , Boland Patrick M , Berim Lyudmyla Derby , Kennedy Timothy , Grandhi Miral , Langan Russell C , Moore Dirk F. , Kane Michael P. , Krishnamurthi Smitha S. , Mayo Skye C. , Kasi Anup , Pimentel Agustin , Carpizo Darren R.
Published: January 2023

103

Background: Novel strategies to improve the efficacy of immune checkpoint inhibitors in microsatellite stable (MSS) mCRC are needed. CV301 is a vector-based vaccine that expresses carcinoembryonic antigen (CEA) and mucin 1 (MUC1), and in a phase II study in resected hepatic limited mCRC significantly improved OS compared with unvaccinated contemporary controls. Methods: In this multi-center randomized phase II study, patients with previously untreated resectable hepatic-limited mCRC were randomized to perioperative nivolumab + mFOLFOX +/- CV301 (Arm B) with a primary endpoint of 3-year OS. Treatment included mFOLFOX-nivo (+/- CV) x 4 cycles followed by resection, then 8 more cycles of mFOLFOX-nivo followed by maintenance nivo monthly for two years in both arms, and CV boosters concurrently with mFOLFOX, and then every 3 months for two years in arm B. Secondary endpoints of ORR (following induction pre-resection), PRR, and safety were determined. Correlative analyses included immune cell quantification using Immunoscore and T-cell clonality. Results: 17 patients were enrolled prior to premature closure for slow accrual (8 arm A, 9 arm B). At the time of data cutoff, 5 patients remained on treatment and no deaths had occurred. One patient was removed from study due to protocol non-compliance. The median age was 61, majority were male (59% vs 41%), and ECOG PS 0-1 (71% 0, 17% 1). All patients had complete surgical resection. Four patients (24%) experienced a SAE related to drug. The TRAE rate was 40.3%,. No AEs delayed/prevented surgical resection. The ORR in arm A was 50% (including 4 CR) and 87.5% in arm B (including 7 CR) (p=0.129, NS). There was no significant difference in pathologic response (p=0.9047). Correlative analyses demonstrated the Immunoscore CD3/CD8 predicted response to mFOLFOX + nivolumab, but did not correlate with response to CV301, though CV301 may induce a shift to predominantly cytotoxic CD8+ T cells. While there was no significant difference in T cell repertoire, clonality, fraction (TCFr) or richness, patients in arm B had significant decreases in blood TCFr and increase in tumor TCFr with treatment; those with CR had higher TCFr and clonality. Conclusions: The addition of CV301 to perioperative nivolumab and mFOLFOX was safe, did not delay or prevent surgical resection, and gave a higher response (p=ns due to sample size). Changes in T cells suggest a vaccine response. Clinical trial information: NCT03547999 . [Table: see text]
Bleeding and thrombotic events in patients with colorectal cancer treated with bevacizumab and receiving novel oral anticoagulants and antiplatelet medications.
Authors: Rho Shinji , Wang Chris , Hosseini Dehkordi Seyed Hamed , Sears Jerod J , Hu Zishuo Ian
Published: January 2023

104

Background: Bevacizumab is a humanized monoclonal VEGF antibody given in combination with fluorouracil-based chemotherapy for metastatic colorectal cancer (mCRC). Many patients with mCRC also have cardiovascular comorbidities requiring anticoagulation or antiplatelet therapy. The bleeding and thrombotic event rates in the setting of concurrent novel oral anticoagulants (NOACs) and bevacizumab treatment in patients with mCRC remain unclear. Methods: 462 patients with mCRC at Barnes-Jewish Hospital were identified between December 1, 2016 and December 1, 2021 and screened for concurrent treatment with bevacizumab and anticoagulant or antiplatelet therapy. Demographic and clinical information was extracted by electronic chart review. Results: 21 patients were identified who received bevacizumab and either apixaban or rivaroxaban for mCRC treatment. Aspirin was prescribed in some of these patients within 3 years of starting apixaban or rivaroxaban. Of the 13 patients who had no history of aspirin prescription, 9 were given apixaban, and 4 were given rivaroxaban while on bevacizumab. 44.4% of the patients who received apixaban experienced bleeding. All these events were epistaxis, and only 25% of the cases resulted in any treatment discontinuation. 75% of the patients who received rivaroxaban experienced bleeding events, which 33.3% of the time resulted in discontinuation of either rivaroxaban or bevacizumab. We also looked at 8 patients who had received aspirin in the last three years: 7 patients were on apixaban, and one was on rivaroxaban while on concomitant aspirin and bevacizumab. 28.6% of the patients who received apixaban with bevacizumab and aspirin experienced an adverse bleeding event that resulted in some form of treatment discontinuation. Meanwhile, the patient who received rivaroxaban with bevacizumab and aspirin experienced a bleeding event that resulted in discontinuation of a medication. No patient experienced any adverse thrombotic events. Conclusions: Patients with mCRC treated with bevacizumab and apixaban with no history of prior aspirin use within three years have a relatively low risk of developing bleeding events that warrant treatment discontinuation. The addition of NOAC to bevacizumab therapy does not appear to increase the risk of adverse thrombotic events.
Comparative study of prognosis of conversion therapy vs palliative therapy without surgery in colorectal cancer with synchronous liver metastasis according to risk classifications.
Authors: Nozawa Hiroaki , Tsushima Tatsuya , Suzuki Nobumi , Fujishiro Mitsuhiro , Kawaguchi Yoshikuni , Hasegawa Kiyoshi , Ishihara Soichiro
Published: January 2023

107

Background: Recent progress in chemotherapy and targeting antibodies has brought an increased opportunity of conversion to curative resection in initially unresectable/metastatic colorectal cancer (CRC). Survival of CRC patients with liver metastasis who underwent conversion therapy was reported better than that of those who received palliative systemic therapy without surgery. However, it is largely unknown whether such patients who undergo conversion therapy can uniformly benefit from the surgical resections. Methods: We retrospectively reviewed 172 patients who received systemic therapy for unresectable CRC with synchronous liver metastasis in our hospital between 2010 and 2020. Patients were divided into ‘Conversion’ group (n = 45) and ‘Non-conversion’ group (n = 127) according to conversion to surgical resection with curative intent. Patients were also divided by pre-treatment Fong’s Clinical Risk Score (CRS), in addition to Grade A, B, or C group according to Japanese Grade Classification for colorectal liver metastasis. Overall survivals (OS) of Conversion and Palliation groups were compared according to these risk classifications. Results: Overall, 3-year OS rate was 76% for Conversion group and 25% for Non-conversion group (p < 0.001). Three-year OS rate for patients in Conversion group with CRS 1-3 was 73%, whereas that for those with CRS 4-5 was 77%. Both were higher than the rates for the counterparts in Non-conversion group (26% and 24%, respectively; both p < 0.001). When confined to Grade A and B of Japanese Grade Classification, 3-year OS rate was 68% for Conversion group and 25% for Non-conversion group (p = 0.002). The 3-year OS rate for the patient groups was 83% and 25% respectively in the analyses of patients classified into Grade C (p < 0.001). Conclusions: Conversion therapy provided a significant survival benefit in CRC patients with liver metastasis regardless of risk groups by the above classifications. Both classifications did not discriminate OS curves well between Conversion and Non-conversion groups in the era of conversion therapy.
A phase II study of CAPOXIRI as a neoadjuvant chemotherapy in patients with locally advanced rectal cancer (Colorectal Cancer Treatment Group, MSCSGO).
Authors: Kagawa Yoshinori , Matsuda Chu , Kudo Toshihiro , Morimoto Yoshihiro , Tei Mitsuyoshi , Ide Yoshihito , Miyoshi Norikatsu , Takahashi Hidekazu , Uemura Mamoru , Takemasa Ichiro , Satoh Taroh , Mizushima Tsunekazu , Murata Kohei , Doki Yuichiro , Eguchi Hidetoshi ,   Multicenter Clinical Study Group of Osaka, Colorectal Cancer Treatment Group (MSCSGO)
Published: January 2023

109

Background: Addition of perioperative multi-agent chemotherapy to the treatment strategy for locally advanced rectal cancer (LARC) may be a promising option. We conducted a multicenter single-arm phase II study to evaluate the safety and efficacy of capecitabine combined with oxaliplatin and irinotecan (CAPOXIRI) as triplet neoadjuvant chemotherapy in patients with LARC. Methods: The key eligibility criteria were as follows: (1) age over 20 years; (2) Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; (3) resectable clinical stage II (T3 or T4 with N0) or III (any T and N1–3), with the primary tumor located within 12 cm of the anal verge. Patients received intravenous oxaliplatin (85 mg/m2) and intravenous irinotecan (150 mg/m2) on day 1 and oral capecitabine (1,000 mg/m2) twice daily on days 1–7 followed by 7 days of rest, repeated every 2 weeks for six cycles. Total mesothelial resection was performed 4–8 weeks after chemotherapy ended. In addition to the treatment protocol, patients received adjuvant chemotherapy for four cycles. The primary study endpoint was the pathological complete response (pCR) rate. We based the sample size of the study described herein on an expected pCR rate of 18% and a threshold pCR rate of 5% to detect differences at a two-sided alpha error of 0.05 and a statistical power of 0.2. Results: Between June 2013 and December 2016, 55 patients were enrolled in the study. Forty-five (83.3%) of the 54 patients who underwent NAC received the full six courses. Fifty-two (94.5%) patients underwent tumor resection. Laparoscopic surgery was performed in 47 (90.4%) patients, and lateral lymph node dissection was performed in 35 (67.3%) patients. Forty-nine (94.2%) patients underwent R0 resection. The pCR rate was 7.7% (95% CI 3.0% to 18.2%). The 3-year local recurrence rate was 3.9%, the 3-year disease-free survival (DFS) rate was 77.3, and the 3-year overall survival rate was 96.0%. NAC-related grade 3/4 adverse event rates were as follows: neutropenia (25.9%), anorexia (13.0%), diarrhea (11.1%) and anemia (7.4%). Conclusions: CAPOXIRI neoadjuvant chemotherapy appears to be feasible and efficacious for patients with LARC. Although neoadjuvant XELOXIRI alone did not yield our expected pCR rate, the local recurrence rate, 3-year DFS and measures of safety met current standards. Clinical trial information: UMIN000009974 .
Effectiveness and safety of encorafenib-cetuximab in BRAFV600E metastatic colorectal cancer: Confidence study.
Authors: Fernandez Montes Ana , Ros Javier , Graña Begoña , García-Alfonso Pilar , Brozos Elena , Melian Marcos , Jiménez-Gordo Ana M. , Martinez de Castro Eva , Busquier Isabel , Gallego Javier , Gravalos Cristina , Covela Marta , Ruiz-Casado Ana , González Flores Encarnación , Safont Mariajose , Cano Juana Maria , Alonso Lopez Carmen , Gomez-Reina Maria Jose , Donnay Olga , Aranda Enrique ,   Confidence Study Group
Published: January 2023

126

Background: BRAFV600E mutant metastatic colorectal cancer (mCRC) has a poor prognosis. The BEACON trial demonstrated an improvement in tumor response, overall survival (OS), and progression-free survival (PFS) when administering encorafenib-cetuximab (EC) to patients (pts) who progressed after 1 or 2 therapy lines. This study provides a retrospective analysis of the effectiveness and safety of EC in the real-world setting in Spain. Methods: This retrospective analysis included BRAFV600E mCRC pts treated with EC in 2nd line treatment, recruited from March to July 2022. The Co-primary study endpoints included effectiveness based on PFS and OS. Secondary endpoints included sociodemographic and clinical characteristics of patients before EC initiation, overall response rate (ORR), and safety. Results: From March to July 2022, 81 evaluable pts were included. Sociodemographic and clinical characteristics are displayed.A median (interquartile range [IQR]) of 6.0 (4.0-13.0) cycles of encorafenib and 6.0 (4.0-14.5) cycles of cetuximab were administered. Median treatment duration was 4.4 (2.6-7.8) months (m) and 4.4 m (2.8-7.6) respectively. The ORR and disease control rate was 33.8 % (CI 95% 23.4-45.5) and 68.8 (CI 95% 57.3 – 78.9) respectively. One (1.2%) pt achieved complete response At data cut-offwith a 9.7 median follow-up, 50 (61.7%) pts had died, all of them due to disease progression. Median (95% Confidence Interval, CI) OS was 12.6 m (8.0-17.3) and median PFS was 5.0 m (3.8-6.2). The 12-m OS and 12-m PFS rates were 54.6% (95% CI, 43.3-65.9) and 19.9% (10.5-29.3) respectively. Pts with neutrophils/lymphocyte ratio (NLR) ≥3 had worse OS (HR, 1.8 95% CI 1.0-3.2; p < 0.049) and worse PFS (HR, 2.3, 1.4-3.8; p < 0.002). Disease progression (86.7%) was the most frequent cause of treatment discontinuation, followed by unacceptable AEs (3.7%). Eleven pts (13.5%) experienced treatment-related graded 3 or 4 AEs, mainly acne (3.7%). Treatment-related deaths were not reported. Conclusions: This study provides real-world data of BRAFV600E mCRC pts treated with EC combination in routine clinical practice in Spain. EC effectiveness and safety were consistent with the results obtained in clinical trials. [Table: see text]
Racial disparities in tumor microbiome in young-onset and average-onset colorectal cancer.
Authors: Dave Heloni M , Sangwan Naseer , Nair Kanika G. , Barot Shimoli V , Liska David , Schmit Stephanie , Khorana Alok A.
Published: January 2023

13

Background: The occurrence of young-onset colorectal cancer (yoCRC) is rising alarmingly, with a disproportionate incidence in Black patients as compared to White. We and others have previously shown differences in tumor microbiomes between yoCRC and average-onset colorectal cancer (aoCRC), but it is unknown if these differences contribute to racial disparities. We therefore analyzed racial differences in the intra-tumoral microbiome of CRC in young adults (<50 years). Methods: We analyzed 277 samples of histologically confirmed cases of stage I-IV CRC patients identified as either non-Hispanic Black or non-Hispanic White, who underwent surgical resection at Cleveland Clinic from year 2000-2020, who consented to a prospective biorepository. Fresh frozen specimens from the primary tumor with paired adjacent nonmalignant tissue were analyzed. The 16s rRNA gene was amplified and sequenced using V4 region primers and Illumina’s MiSeq system. Using DADA2, the quality filtered 16S rRNA amplicon reads were clustered and annotated as amplicon sequence variants (ASVs). The abundance count matrix was analyzed for alpha and beta diversity and differential abundance analysis (DAA) using Phyloseq package. Statistical tests included analysis of variance (ANOVA), permutational multivariate analysis (PERMANOVA), linear regression and Wilcoxon test. DAA and correlation analysis were controlled for false discovery rate using Benjamini Hochberg correction. Results: Differential abundance analysis highlighted key differences in the microbiome composition of Black and White patients with yoCRC. Amongst Black patients, the most prevalent taxa were Limosilactobacillus, Bacillus, Staphylococcus, Listeria and Akkermansia, whereas amongst White patients the most prevalent taxa were Enterococcus and Escherichia-Shigella (Table). Microbial profiles were also significantly different between Black patients with yoCRC and aoCRC and between White patients with yoCRC and aoCRC. At ASV level, the microbiome of Black yoCRC is more similar (R2 =0.87) to Black aoCRC, in comparison to white yoCRC (R2=0.57). Conclusions: We found significant differences between the intra-tumoral microbiome of yoCRC in the United States by race. Future epidemiologic studies and public health interventions need to account for these differences to reduce risk of yoCRC across various US populations. [Table: see text]
The impacts of initiating regorafenib with reduced dose on treatment outcomes in metastatic colorectal cancer.
Authors: Kawakami Takeshi , Harada Kazuaki , Ogata Takatsugu , Hu Qingjiang , Fushiki Kunihiro , Oshima Kotoe , Kadowaki Shigenori , Taniguchi Hiroya , Muro Kei , Nakanishi Ryota , Ando Koji , Nambara Sho , Yamamura Takahiro , Kawamoto Yasuyuki , Komatsu Yoshito , Oki Eiji , Masuishi Toshiki , Yamazaki Kentaro , Yuki Satoshi
Published: January 2023

133

Background: Since the results of the ReDOS study were published, starting regorafenib (REG) at a reduced dose is now considered a treatment option for patients with metastatic colorectal cancer (mCRC). However, the impact of starting REG at a reduced dose on treatment outcomes in the real-world setting has not been fully investigated. Methods: We retrospectively analyzed patients who received REG for mCRC at 4 institutions between May 2013 and December 2020. These patients were divided into two groups: those who started REG before (Period A) and after (Period B) the ReDOS study publication (May 2018). The treatment outcomes between Period A and B were compared in this analysis. Results: A total of 573 patients were evaluated (385 in Period A and 188 in Period B, respectively). In Period B, significantly more patients started REG with reduced dose (34.3% vs. 75.5%, p< 0.001). The median time to first dose reduction was 32.0 days [95% CI: 29.1-34.9] in Period A and 61.0 days [95% CI: 33.7-88.9] in Period B, which was significantly longer in Period B (HR = 0.685, p= 0.003). Both any grades and ≥grade3 hand foot skin reaction (HFSR) were significantly less frequent in Period B than in Period A (any grades: 65.5% vs 54.8%, p= 0.017, ≥grade3: 21.3% vs 14.4%, p= 0.054). The median time to onset of any grades HFSR was 16.0 days [95% CI: 13.6-18.4] in Period A and 28.0 days [95% CI: 15.6-40.4] in Period B, which was significantly longer in Period B (HR = 0.738, p= 0.007). The median overall survival was 6.7 months [95% CI: 5.9-7.4] in Period A, and 5.4 month [95% CI: 4.3-6.5] in Period, respectively (HR = 1.105, p= 0.281). The median progression free survival was 2.0 months [95% CI: 1.9-2.1] in Period A and 2.1 months [95% CI: 1.8-2.4] in Period B, respectively (HR = 1.064, p= 0.498). Conclusions: Our results suggest that starting REG at a reduced dose may contribute to reducing the frequency and delaying the onset of HFSR, whereas it may not affect efficacy.
Short-course radiotherapy in rectal cancer: A single-center experience in Argentina.
Authors: Tissera Natalia Soledad , Freile Berenice , Luca Romina , Pedraza Ivana Inés , Esteso Federico , Enrico Diego Hernán , Waisberg Federico , Galli Mariana , Chacon Carolina , Sanchez Loria Fernando , Huertas Eduardo , Chacon Matias Rodrigo , O'Connor Juan Manuel
Published: January 2023

146

Background: Short-course radiotherapy (SCRT) is an option in the neoadjuvant setting of resectable stage II-III rectal cancer, as well as in stage IV disease for local control without delay to initiate systemic treatment. Short-course radiotherapy is reported to be a comparable strategy for locally advanced rectal cancer. Limited data exist regarding the use of short-course radiation therapy when used as part of a non-surgical watch and wait approach. Methods: This is a retrospective analysis of all patients that underwent SCRT for rectal cancer at the Alexander Fleming Institute from 3/2014 to 6/2022. Results: 44 patients were treated with SCRT, 29 (66%) were male, with a median age of 59 years (46-73). Most of the patients had stage IV disease (26, 59,1%) followed by clinical stage II-III (18, 40,9%). 30 (68%) were localized in the middle with 14 (32%) in the lower rectum, by MRI imaging. In locally advanced disease 5/18 had T4 disease and 7/18 had N≥2. 14/18 patients (89%) underwent SCRT followed by consolidation chemotherapy (ChT) and 4 (11%) had induction ChT followed by SCRT. In metastatic disease 14/26 patients (53.84%) underwent SCRT followed by consolidation ChT, 10 (38.46%) had induction ChT followed by SCRT, and 2 (7.7%) received only SCRT. 29 (65.9%) of patients underwent surgery. 17/29(58.6%) had metastatic disease and 12/29 (41.4%) had locally advanced disease. Pathological response rates in operated patients were 2 (6.9%). 8 (18.2%) cases had a clinical complete response (cCR) (n=6 stage II-III and n=2 stage IV). Five (27.7% of the locally advanced group) patients with cCR underwent watch and wait with 1 local recurrence after 14 months. The remainder is disease free with a median follow-up time of 20 months (IC 95%: 15.14-24.85). Those that underwent SCRT following chemotherapy were more likely to have AEs compared to those that had chemotherapy following SCRT (11/30, 36.7% vs 25%, p=0.02). Conclusions: Our work shows that in a subgroup of patients diagnosed with LARC treated with SCRT followed by Chemotherapy, surgical treatment could be deferred after achieving a complete clinical response. The shorter time involved by SCRT allowed for less treatments with similar toxicity to long-course treatment regimens. SCRT is a reasonable option for local disease control in stage IV disease.
Efficacy and safety of neoadjuvant immune checkpoint inhibitors in patients with localized mismatch repair deficient colorectal cancer: A systematic review.
Authors: Grewal Udhayvir Singh , Vora Kruti Bhagirath , Parikh Aparna Raj , Mahipal Amit , Chakrabarti Sakti
Published: January 2023

149

Background: Clinical data demonstrating remarkable anti-tumor activity of immune checkpoint inhibitors (ICI) in patients with mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) and preclinical data suggesting enhanced efficacy of ICIs in the neoadjuvant setting than in the adjuvant setting led to numerous studies with neoadjuvant ICI in various tumor types including in dMMR CRC. We performed a systematic literature review of the published studies reporting the efficacy and safety of neoadjuvant ICIs in patients with localized dMMR CRC. Methods: Medline and Embase were searched for eligible case reports, case series, and clinical trial reports. Eligibility criteria included: 1. patients aged 18 years or older, 2. localized dMMR CRC, and 3. received neoadjuvant therapy primarily with ICI. Patients receiving radiation or chemotherapy along with ICI were excluded. The systematic review was conducted according to the PRISMA harms guidelines. Results: The database search yielded 143 citations which were reviewed by 3 authors (UG, KV, and SC), and 14 citations fulfilled all criteria for inclusion. The analysis included 173 patients with colon cancer (CC) and 19 with rectal cancer (RC). Among the patients with CC, 41 (24 %) received single-agent programmed death 1 (PD-1) blocker, and 132 (76 %) received dual blockade with an anti-PD-1 agent plus an anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) agent. Resection was performed in 171/173 (99%) patients, and 117/171 (69%) achieved complete pathological response (pCR). After median follow-up ranging between 8 and 15 months, none of the patients experienced cancer relapse. Among patients with RC, 16/19 (84%) received a PD-1 blocker, and 3 (16%) received dual PD-1 plus CTLA-4 blocker. Complete clinical response (cCR) was reported in 14/19 (74%) patients, and of the 5 patients who underwent surgery, 4 (80%) achieved pCR. All patients remained progression-free after median follow-up ranging from 6 to 12 months. Cancer progression or death on neoadjuvant ICI was not reported in any studies with CC or RC patients, and only two studies reported grade 3+ toxicity in 3% of CC patients. Conclusions: Neoadjuvant therapy with ICIs results in a remarkably high rate of clinical and pathological tumor regression with negligible safety concerns in patients with dMMR localized CRC. Well-designed clinical trials with long-term follow-up are needed to evaluate the organ-sparing potential of neoadjuvant ICI therapy in patients with dMMR CRC.
Impact of COVID-19 pandemic on diagnosis, staging, and outcomes of patients with early-onset colorectal cancer.
Authors: Martinez-Perez Daniel , Viñal David , García Cuesta Jose Ángel , Rueda-Lara Antonio , Ruiz-Gutierrez Iciar , Jiménez-Bou Diego , Peña-Lopez Jesus , Martin-Montalvo Gema , Alameda-Guijarro Maria , Gutiérrez-Sainz Laura , Barbachano Antonio , Rodriguez-Cobos Javier , Bustamante-Madrid Pilar , Larriba Maria Jesús , Fernandez-Barral Asuncion , Burgos Aurora , Prieto-Nieto Maria Isabel , Pastrian Laura Guerra , Gonzalez-Sancho Jose Manuel , Rodriguez Salas Nuria
Published: January 2023

15

Background: Although we seem to be recovering from COVID-19, we are now facing the long-term consequence of the pandemic on vulnerable subgroup of patients such as patients with early-onset colorectal cancer (EOCRC). We aim to study how the COVID-19 pandemic affected the diagnosis and clinic-pathological characteristics, treatment and outcomes of patients with EOCRC. Methods: This is an observational retrospective study including patients with EOCRC diagnosed between September 2016 and August 2021 at Hospital Universitario La Paz, Madrid, Spain. Two cohorts were stablished: before and after March 14, 2020, the day of the first lockdown in Spain. Results: A total of 1409 patients with CRC were included. Of those, 5,2% were EOCRC (n=75). Fifty-five (73%) and 20 (27%) were diagnosed pre, and post pandemic. The rate of EOCRC diagnosis per month was 1,8 and 1,1 in the pre and postpandemic group, respectively. Fifty percent of patients in the postpandemic group were diagnosed with metastatic disease, while only 29% had stage IV at diagnosis in the prepandemic subgroup (P = 0,09). High tumor budding, surgical margins affected, lymphovascular, and perineural invasion were also pathological features more observed in the postpandemic subgroup, although results are not statistically significant. The differences between both groups are depicted. After a median follow-up of 23 months (33 and 14 months in the pre and postpandemic group, respectively), 11 patients have died (15%). Median overall survival (OS) was not reached in either group. At 12 months, 94% and 89% of patients were alive in the pre and postpandemic group, respectively. Conclusions: COVID-19 has influenced the diagnosis and staging of patients with EOCRC. Long-term follow-up is needed to assess the survival in this population. The role of primary care in the diagnosis and early referral of these patients is, more than ever, crucial. [Table: see text]
Efficacy and safety of fruquintinib plus mFOLFOX6/FOLFIRI as first-line therapy in advanced metastatic colorectal cancer (mCRC).
Authors: Zhou Fuxiang , Wen-bo Wang , Xia Ling , Dai Jing , Wu Han , Yang Lei , Xiong Zhiguo , Gong Jun
Published: January 2023

152

Background: Fruquintinib is a highly selective, and potent oral inhibitor of VEGF receptor 1, 2, 3 and has been recommended as a third-line treatment for mCRC patients (pts) in China because of its low toxicity, favorable ORR and survival benefit. FOLFOX/FOLFIRI is the preferred chemotherapy regimens of first-line for mCRC pts according to the NCCN guideline. Our study aimed to investigate the efficacy and safety of fruquintinib plus mFOLFOX6/FOLFIRI as first-line therapy in advanced mCRC pts. Methods: In this prospective, open-label, multi-center, single-arm phase 2 study (NCT05004441), pts who are diagnosed with unresectable mCRC, without prior systemic threated are recruited. RAS/BRAF status should be detected to exclude BRAF mutations before enrollment. Pts receive fruquintinib (3mg, QD, PO, Q4W) in combination with mFOLFOX6/FOLFIRI (Q2W) for up to 8 cycles. Pts with SD or above are followed by maintenance therapy (fruquintinib 3mg, QD, PO, Q4W, capecitabine 850mg/m2, BID, PO, D1-7, D15-21, Q4W) until disease progression or intolerable toxicity. The primary endpoint is objective response rate (ORR), and secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety. Results: Based on a data cutoff of September 2, 2022, 19 pts have been enrolled and treated, of which 13 pts have efficacy evaluation data. Media age is 60 (range: 50-73) years and 62% pts are male. 7 (54%) pts harboring RAS mutations while the remaining pts are wild-type (wt). 54% treated with mFOLFOX6. At a median follow-up of 5.9mo, all 13 pts are still on treatment. In best overall response assessment, the ORR is 77%, with 10 (77%) partial response (PR). Stable disease (SD) is 3 (23%) with a DCR of 100%. Median PFS has not yet reached. Safety profile exhibited that the regimen is tolerable and mainly grade 1/2. Grade 3 treatment-related adverse events (TRAEs) are neutrophil count decreased (23%), GGT increased (15%), leukopenia, AST increased and hypertension accounted for 1% respectively. No pts have serious adverse events. Conclusions: Combination treatment with fruquintinib plus mFOLFOX6/FOLFIRI as the first-line therapy followed by fruquintinib plus capecitabine maintenance in advanced mCRC pts shows promising efficacy and manageable safety profile. Longer follow up data with PFS, and OS will be presented. Clinical trial information: NCT05004441 .
Phase Ib study of dabrafenib, trametinib, irinotecan and cetuximab in BRAF V600E-mutated metastatic colorectal cancer.
Authors: Chen Yungchang , Li Xiaoqian , Yuxin Man , Hu Hai , Wang Liyang , Zhang Zhixuan , Chen Ping , Liu Yang , Lu Jin , Lin Tongyu
Published: January 2023

156

Background: The low efficacy of single-agent BRAF inhibitor in metastatic colorectal cancer (mCRC) is usually due to EGFR feedback upregulation caused by BRAF blockade. Therefore, multi-drug combination therapy with BRAF inhibitor has been tried. Here, we reported the preliminary results of quadruple therapy with dabrafenib, a selective BRAF inhibitor, trametinib, a selective MEK inhibitor, irinotecan and cetuximab in patients with BRAF V600E-mutated mCRC. Methods: This was an ongoing phase Ib study, patients with mCRC who relapse or refractory to standard treatments were enrolled. Patients were treated with dabrafenib (150mg/150mg doses orally twice daily), trametinib (2mg orally once daily), irinotecan (80mg/m2 weekly) and cetuximab (400mg/m2 in first dose and 250mg/m2 weekly). Treatment was continued until disease progression, development of unacceptable toxicity, or drawal of consent. The primary end-point was disease control rate (DCR), and the secondary end-points included progression-free survival (PFS) and duration of disease remission (DOR). This trial is registered with Chinese ClinicalTrials.gov, number ChiCTR2200063316. Results: From July 2018 to January 2021, 10 patients were enrolled. The median age was 53.5 (age 25-65), nine with colon cancer and one with rectal cancer. The most common adverse events (AEs) (50% or more) were fatigue, fever, rash, vomit, leukopenia, anemia, ALT elevation, and AST elevation. Four patients suffered rash which was the most common severe AE (SAE). Two patients presented with grade 3/4 anemia. Only one patient suffered grade 3/4 AEs with nausea and vomit. The DCR was 90% (9/10). After a median follow-up of 19.7 months, the median PFS was 7.5 months (range 1.8-32.4 months). The median DOR was 5.2 months (range 0-27.7 months). Conclusions: Dabrafenib, trametinib, irinotecan and cetuximab has tolerable toxicity and promising antitumor activity in BRAF V600E-mutated mCRC. This regimen warrants a further phase II clinical trial. Clinical trial information: ChiCTR2200063316 . [Table: see text]
A systematic review to assess the efficacy of HER2-targeted treatment regimens in HER2-positive metastatic colorectal cancer (mCRC).
Authors: Bakhtiar Muhammad , Gholami Sepideh , Saeed Anwaar
Published: January 2023

166

Background: Recently, there has been a breakthrough in the treatment and disease control of HER-2 positive mCRC using Trastuzumab (TRA) +Tyrosine Kinase inhibitor (TKI) regimens and regimens with trastuzumab based antibody drug conjugates (ADCs). Methods: A total of 14 randomized controlled trials and single arm clinical trials were collected from PubMed, Cochrane library, and Embase. 7 trials were excluded for being duplicate, irrelevant or because of lack of response from the trial researchers. Data from the remaining 7 articles was extracted either from the full publication or from researchers for undergoing studies. Trials using similar drug combinations were added up and results were reported cumulatively. Results: The data demonstrate an ORR of 30% or greater with the ADC, TRA deruxtecan or TRA+Tucatinib regimen with the Tucatinib combination being the most efficacious (38.10%), followed closely by the Deruxtecan ADC (36.99%). Promising disease control rate (DCR) was observed with all the combinations with TRA-Ematasin + Pertuzumab leading the charts (77.40%). TRA-Lapatinib provided the longest PFS (16.75 months) followed by TRA-Tucatinib (8.2 months) (Table). Most common treatment related adverse events (AEs) were fatigue, nausea, vomiting, diarrhea and dermatitis. More nausea/vomiting reported with TRA-deruxtecan (64.4%), while more diarrhea reported with TRA-lapatinib (81%) and TRA-tucatinib (52.3%). Dermatitis was reported mostly with TRA-lapatinib (44%) and TRA-tucatinib (17.4%). Conclusions: Our analysis shows that combination treatment with TRA-Deruxtecan and TRA-tucatinib are associated with the highest ORR and DCR in HER2+ mCRC. Long term data are needed to define clinical efficacious based on survival endpoints.[Table: see text]
Impact of Lynch syndrome, BRAFV600E, and RAS mutations on outcomes in MSI/dMMR metastatic colorectal cancer (mCRC) treated with immune checkpoint inhibitors (ICI): Analysis of combined international cohorts.
Authors: Colle Raphael , Lonardi Sara , Cachanado Marine , Overman Michael J. , Elez Elena , Fakih Marwan , Corti Francesca , Jayachandran Priya , Svrcek Magali , Dardenne Antoine , Duval Alex , Cohen Romain , Pietrantonio Filippo , Andre Thierry
Published: January 2023

171

Background: ICI have demonstrated efficacy in patients (pts) with MSI/dMMR mCRC . Lynch (LS) vs sporadic (Sp) status, BRAFV600E and RAS mutations (mt) are known factors of clinical and molecular heterogeneity in this population. We aimed to evaluate the prognostic value of these parameters in ICI-treated MSI mCRC pts. Methods: Pts are drawn from international cohorts (France, Italy, Spain, and USA). Pts were considered to have cancer linked to LS only in case of determined germline mutation and Sp in case of loss of MLH1/PMS2 protein expression associated with BRAF V600E mutation and/or hypermethylation of MLH1 promoter, or in case of biallelic somatic mutations of MMR genes. Survival analyses: progression-free survival (PFS) per iRECIST criteria and overall survival (OS) were adjusted on prognostic modifiers, selected on unadjusted analysis (p < 0.2) in case of limited number of events. Results: On the 466 pts included, 112 (24%) received ICI in first line, 305 (65%) received anti-PD1 alone, 161 (35%) anti-PD1 plus anti-CTLA4, 129 (29%) had BRAFV600Emt and 153 (34%) RASmt. Median follow-up was 24.0 months. In adjusted analysis of the whole population (n=466; 186 PFS events and 143 OS events), no association with PFS and OS was observed for BRAFV600E mt (PFS HR 1.20 [0.80 to 1.79], p=0.372; OS HR 1.06 [0.66 to 1.70], p= 0.811) and RASmt (PFS HR 0.93 [0.64 to 1.36], p= 0.712; OS HR 0.75 [0.48 to 1.17] p= 0.202). Adjusting factors were age, ECOG status, number of prior chemotherapies, treatment type (bi vs monotherapy), sidness (right vs left + rectum), primary tumor surgery. Concerning the population with determined Lynch status (n= 242; 83 PFS events and 54 OS events), PFS results are displayed. The analysis of impact of LS was not adjusted on BRAFV600E mutational status due to collinearity. In adjusted analysis, LS improved PFS compared with Sp (HR = 0.49, 95%CI (0.25 to 0.96), p = 0.036). Adjusted HR for OS was 0.56 without reaching significance 95%CI (0.25 to 1.22), p = 0.143. Conclusions: In this analysis of ICI-treated MSI/dMMR mCRC pts, RAS/BRAFV600E mutations are not associated with survival while Lynch syndrome pts demonstrated improved PFS. [Table: see text]
Metabolomic differences in young-onset versus average-onset colorectal adenocarcinoma.
Authors: Jayakrishnan Thejus , Farha Nicole , Mariam Arshiya , Rotroff Daniel Miller , Aucejo Federico , Barot Shimoli V , Conces Madison , Nair Kanika G. , Krishnamurthi Smitha S. , Schmit Stephanie , Liska David , Khorana Alok A. , Kamath Suneel Deepak
Published: January 2023

174

Background: Novel deleterious effects of environmental exposures may play a role in the rising incidence of young-onset colorectal cancer (yoCRC). We used metabolomics to assess differences between yoCRC and average-onset CRC (aoCRC), in comparison to healthy controls, which may suggest certain exposure risks. Methods: Patients with stage I-IV CRC and healthy controls were identified from prospective biobanks and categorized based on age<50 years (yoCRC or young controls) or age>60 years (aoCRC or older controls). Serum metabolites were profiled using GC-TOF mass spectrometry. Differential abundance of metabolites was investigated using unadjusted logistic regression. Metabolic pathway analysis was performed using Metaboanalyst 5.0. All p-values were adjusted for multiple testing (false-discovery rate, FDR p<0.20 considered significant). Results: The study population comprised 170 CRC patients (66 yoCRC and 104 aoCRC) and 49 healthy controls (34 young and 15 old). Association analyses revealed four differentially abundant metabolites: citrate (FDR p=0.04), cholesterol (0.14), and two unidentified metabolites (UM). Metabolic pathways significantly altered in yoCRC vs. aoCRC included: carbohydrate metabolism (citrate cycle, FDR p=0.11), carbohydrate biosynthesis (glyoxylate and dicarboxylate metabolism, FDR p=0.03), amino-acid metabolism (alanine, aspartate, and glutamate metabolism, FDR p=0.04, arginine biosynthesis, FDR p=0.04, and amino-acid t-RNA biosynthesis, FDR p=0.04). There were no significant metabolomic differences between young and older controls. Conclusions: We identified significant differences in the citrate cycle - a core pathway of cellular metabolism and associated with colorectal cancer. Metabolomic differences in pathways of carcinogenic significance (aspartate) and environmental exposures (arginine and dietary red meat) were also noted, suggesting potential relationships with younger age of CRC onset. The study provides future directions for more precise analyses with a larger sample size for healthy controls and adjusting for confounders. [Table: see text]
Molecular characterization of metastatic colorectal cancer (mCRC) in patients (pts) treated with cetuximab and pembrolizumab.
Authors: Fountzilas Christos , Rosario Spencer , Withers Henry G. , Mukherjee Sarbajit , Bajor David L , Saltzman Joel N. , Wang Chong , Attwood Kristopher , Knudsen Erik S. , Witkiewicz Agnieszka K , Iyer Renuka V. , Boland Patrick M
Published: January 2023

178

Background: Anti-EGFR therapy has the potential to increase a localized anti-tumor immune response. We recently published the results of a phase Ib/II trial of the anti-EGFR antibody cetuximab in combination with the anti-PD1 antibody pembrolizumab in pts with advanced, RASwt CRC (PMID: 34645646). Despite its partial local immunologic efficacy, this combination of cetuximab and pembrolizumab was inactive. Here we present the results of comprehensive molecular characterization of pts with tumors amenable to DNA and RNA sequencing. Methods: Forty-two pts with RASwt mCRC were treated with cetuximab plus pembrolizumab. Archival or fresh tumor samples were obtained at baseline and, in select patients, on-treatment. Tumor samples underwent targeted DNA sequencing and whole transcriptome sequencing. Gene set enrichment analysis (GSEA), metabolic dysregulation assessment, and immune deconvolution were performed. Genomic data were linked to clinical outcomes. Results: Eighteen pts had tissue available for dual DNA/RNA extraction and sequencing. Of these, 10 had available matched on-treatment tumor samples. The most common mutations detected in protein coding regions were TP53 (14 pts), ERBB4 (5 pts), CDKN2A and APC (6 pts each). There were no statistically significant differences in progression-free survival (PFS) in pts with and without resistance-associated mutations (i.e., RAS, MET, ERBB4). Further, there was no significant difference associated with the consensus molecular subtype (CMS). However, when we compared patients with stable/increased tumor change percentage to those with decreased tumor change percentage, we found downstream transcriptional differences associated with altered metabolism, and in particular lipid and amino acid metabolism. Conclusions: We identified a significant number of patients with mutations predicting resistance to either or both cetuximab and pembrolizumab; however, none were associated with survival. However, we did identify metabolic pathways of interest, which may be associated with response to therapy. It is important to note, our analysis is limited by the small number of specimens (Trial registration NCT02713373). Clinical trial information: NCT02713373 .
Use of distinct molecular signatures of appendiceal cancer subtypes to assess biomarker development.
Authors: Tan Wan Ying , Tian Melissa , Ruzgar Nensi , Hengartner Astrid , Sailo Bethsebie , Ang-Olson Olivia , Ubas Airol , John Nithyla , Yaghoobi Vesal , Tang Haoyu , Sharma Anup , Nalbantoglu ILKe , Ahuja Nita
Published: January 2023

189

Background: Appendiceal Neoplasms are diverse entities which have a variety of clinical presentations, histologic subtypes, biologic behavior, and patient outcomes. Advanced disease at initial diagnosis is not uncommon and therapeutic options are limited. This study aims to identify potential targets to develop epigenetics-based therapeutics/biomarkers. Methods: Archival (FFPE) specimens were collected from 25 patients with histologically confirmed and subtyped appendiceal neoplasia and 16 age-matched non-neoplastic controls. Four appendiceal neoplastic processes identified: Low grade appendiceal neoplasm (LAMN), pseudomyxoma peritonei (intra-peritoneal spread of LAMN), conventional-type adenocarcinoma and goblet cell adenocarcinoma. Gene expression profiling was performed using the HTG EdgeSeq Oncology Biomarker panel. Differentially expressed genes (DEGs) were selected with cut-off threshold FDR<0.05 and analyzed using Qlucore Explorer and functional analyses via Ingenuity Pathway Analysis (IPA). Results: Four appendiceal neoplastic processes identified: pseudomyxoma peritonei (20%), low-grade appendiceal mucinous neoplasm (24%), adenocarcinoma (24%), and goblet cell adenocarcinoma (32%). Unsupervised hierarchical clustering identified 498 DEGs (424 up, 74 down) between all appendiceal cancer versus age-matched controls that showed enrichment in B-cell inflammatory signaling, senescence, cell cycle regulation, PI3K/AKT signaling, cell cycle checkpoint control pathways, and sets relating to NANOG in stem cell pluripotency (all p0.001). G1/S checkpoint, apoptosis, ATM, and PTEN signaling are downregulated (p0.001). TP53, E2F1, IL6, IFNG, TNF, and HGF (p0.001) regulated overlapping genes. Four-subgroups comparison found 67 DEGs involved in T-helper cell differentiation, immune-mediated apoptosis, T-cell fatigue, and PD1/PDL1 signaling to be dysregulated (p0.001). IFNG, FGF2, POU5F1, TNF, and MYC (p0.001) were upstream regulators. Conclusions: In this study, downregulated gene expressions in appendiceal cancers are related to cell proliferation and death control mechanisms, with a trend towards overexpression of inflammatory and cell cycle pathways. It is postulated that genes involved in these pathways are hypermethylated. More research is being undertaken on epigenetics-based biomarkers for diagnosis and prognosis. Given PI’s decades of experience in biomarker research, we aim to develop a "single blood test" to expand bedside monitoring alternatives that align with the National Cancer Moonshot Initiative to discover cancer early, when the likelihood of a cure is highest.
Genomic landscape of acquired resistance to targeted therapies in metastatic colorectal cancer (mCRC).
Authors: Harrold Emily , Keane Fergus , Sinopoli Jenna Cohen , Diaz Luis A. , Cercek Andrea , Yaeger Rona
Published: January 2023

190

Background: Therapies targeting oncogenic driver mutations have radically altered the treatment paradigm for mCRC and improved outcomes. New selective inhibitors aim to expand the portion of mCRC with targetable alterations. However, these drugs are limited by a relatively short duration of response before the emergence of acquired resistance. We hypothesized that both the putative resistance mechanism (mutations (MUT) versus copy number alterations (CNA)) and the clonality of the emergent mutations may influence time to resistance. Methods: We screened the MSKCC IMPACT dataset of 5,403 MSS (microsatellite stable) CRC patient samples (3,704 primary sequenced, 1669 metastatic site sequenced) for patients (pts) who had been treated with targeted therapies against EGFR, BRAF, KRAS G12C, or HER2 with tissue or liquid biopsy samples profiled at progression. Clinicopathological features and acquired genomic changes emerging at resistance were assessed. Results: 42 pts were identified with targeted oncogenic drivers consisting of BRAF V600E (17 pts), EGFR (12 pts), KRAS G12C (11 pts), and HER2 (2 pts). Progression specimens analyzed consisted of tissue biopsies in 17 pts (40%) and circulating free DNA (cfDNA) in 21 pts (50%), 4 pts had both tissue and cfDNA analyzed at progression. Median time on targeted therapy (TOT) was 7.1 months (95% CI: 5.6-8.5). Putative resistance alterations were identified in 33 pts (79%) (18 cfDNA, 11 tissue, 4 both cfDNA and tissue) and consisted of MUT alone in 30%, MUT+CNA or rearrangement 70%. Concurrent PIK3CA mutations in pre-treatment tissues were identified in 17 pts (40%) and did not associate with TOT (p=0.68); acquired PI3K pathway alterations were identified in 5 pts (12%), including 2 pts who had baseline tumor PIK3CA mutation. Number of putative resistance alterations ranged from 0-13, with multiple resistance alterations identified in 18 pts (15 ctDNA, 3 tissue), and these could be categorized into three groups: one alteration (15/33; 45%), 2-4 alterations (8/33; 24%), and ≥5 alterations (10/33; 30%). Evaluating TOT by type of alteration: MUT only: 9.8 months, MUT+ CNA+/- rearrangement: 6.6 months (p=0.0079). Evaluating TOT by number of alterations: >4 alterations: 6.1 months versus 1-4 alterations: 8.9 months (p=0.012), or 1 alteration: 8.0 months versus >1 alteration: 6.7months (p= 0.5). There was no significant difference in TOT when evaluating by clonality of mutations, where subclonal was defined as <5% of highest variant allelic fraction (clonal vs subclonal, 9.7 vs 6.7 months, p= 0.09). Fusions identified at time of resistance (involving BRAF in 2 pts, MET in 1 pt, RET in 1 pt) occurred with ≥5 alterations in 3 of 4 pts. Conclusions: Presence of CNA and ≥5 new alterations at resistance were associated with shorter TOT, and there was a trend for subclonal alterations and shorter TOT. New approaches that target underlying mechanisms for these changes may extend TOT.