First-line Palliative Chemotherapy Research Articles

Abstract 5164: cell-free DNA (cfDNA) fragment size as a potential quantitative biomarker for metastatic colorectal cancer (mCRC)

Abstract Introduction: The fragment size of cfDNA derived from tumor cells are known to be shorter than that from normal cells for not yet precisely known mechanisms. We hypothesized that the fragment size of cfDNA can be utilized to reliably estimate tumor burden in patients with mCRC undergoing palliative chemotherapy. Methods: cfDNA sequencing data from mCRC patients receiving first-line palliative chemotherapy at Seoul National University Hospital (Seoul, Korea) were used for this analysis. The patients were enrolled in a main study evaluating the dynamic changes of circulating tumor DNA mutational profiles during chemotherapy. Blood samples were obtained prior to chemotherapy and after every four cycles of chemotherapy until disease progression. cfDNA sequencing data from normal individuals were used as control data. cfDNA sequencing for both cancer patients and normal individuals were performed using AlphaLiquid® 100 target capture panel (IMBdx, Inc., Seoul, South Korea). AlphaLiquid® 100 is a tumor agnostic panel consist of 106 genes, including 10 gene fusion and MSI. Based on the panel sequencing data, the genetic alterations and the fragment size of cfDNA were calculated. The fragmentation ratio was defined by the ratio of the read fragment proportion in size range P1 (100 - 155 bp) and P2 (160 - 180 bp). Results: cfDNA sequencing data from 280 plasma samples from 62 mCRC patients and 50 healthy controls were used for analysis. Compared to cfDNA from healthy controls, the cfDNA fragment sizes from mCRC patients were significantly shorter (169.585 bp vs. 173.964 bp; p < 0.001). Comparing the fragment sizes by the mutational status, the fragment sizes of alleles with detected somatic mutations were significantly shorter than those with reference alleles (mean fragment size 155.853 bp in alleles with somatic mutations vs. 160.613 bp in reference alleles; p < 0.001), but such difference was not observed with germline mutations (mean fragment size 160.911 bp in alleles with germline mutations vs. 159.889 bp in reference alleles; p = 0.992). Further, the clonality inferred from the variant allele frequency (VAF) of somatic mutation was negatively correlated with the size of the cfDNA fragment. The read fragment proportion in size range P1 was significantly associated with the clonality (r = 0.86, p <0.001). We calculated the mean size of DNA fragment and the fragmentation ratio with each longitudinal sample. The fragmentation ratio was found to decrease with chemotherapy in responders and re-increase at the time of resistance to chemotherapy. Conclusions: The fragmentation ratio calculated from cfDNA in mCRC patients can represent tumor burden in dynamic samples and potentially can be used as a biomarker. Citation Format: Jun-Kyu Kang, Hwang-Phill Kim, Yoojoo Lim, Su Yeon Kim, Tae-You Kim. cell-free DNA (cfDNA) fragment size as a potential quantitative biomarker for metastatic colorectal cancer (mCRC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5164.

P-187 Epidermal growth factor receptor inhibitors (EGFRi) in patients with left-side, RAS wildtype metastatic colorectal cancer: Clinician use and outcomes for patients

Current treatment for metastatic colorectal cancer (mCRC), includes anti-epidermal growth factor receptor inhibitors (EGFRi) for RAS wildtype cancers. With improved outcomes has come added complexity for clinician treatment selection and sequencing. Head-to-head studies support first-line EGFRi use over bevacizumab in combination with chemotherapy for patients with a left-side primary. In January 2015, the EGFRi cetuximab gained government approval for first-line use in Australia, with routine RAS testing increasing in turn. In clinical practice, around 50% of patients do not receive second-line treatment, suggesting many patients miss out on this treatment option if reserved for second-line and later treatment. Clinical data from July 2009 to July 2021 was reviewed from TRACC (Treatment of Recurrent and Advanced Colorectal Cancer), a prospective, comprehensive, multi-site Australasian registry, to identify patients with RAS wildtype, left-side primary mCRC who received first-line treatment. Intent (curative vs palliative), biologic use and chemotherapy backbone were described over time. Patients who received first-line palliative intent doublet chemotherapy who were ECOG 0 or 1 at diagnosis were further characterised. Second-line treatment groups were analysed according to biologic and sequence used. Fisher’s exact test was used for significance tests and Kaplan Meier curves for survival analyses. 800 patients had left-side primary RAS wildtype mCRC and received first-line chemotherapy. 166 (20%) received first-line EGFRi plus chemotherapy, 352 (43%) received bevacizumab plus chemotherapy, and 282 (35%) received chemotherapy alone. Patients diagnosed after government EGFRi approval in January 2015 were more likely to be treated with first-line EGFRi plus chemotherapy than first-line bevacizumab plus chemotherapy (36% vs 30%, p < 0.001). While patients receiving first-line EGFRi were younger (60 vs 62 years, p=0.006) with fewer comorbidities (Charlson Comorbidity Index ≥ 3 in 13% vs 20%, p=0.048), ECOG status, de novo metastatic disease, deficient mismatch repair status or site of metastases were not different between the two groups. Overall, 148 (19%) left-side primary RAS wildtype patients never received any biologic agent. Of the palliative intent cohort (n = 490), median progression-free survival (PFS) was 11.6, 10.5 and 9.2 months for EGFRi plus doublet chemotherapy, bevacizumab plus doublet chemotherapy, and doublet chemotherapy alone respectively. EGFRi plus doublet chemotherapy had significantly longer PFS than doublet chemotherapy alone (HR 0.70 [0.52 - 0.95], p=0.022), but did not reach statistical significance compared to the bevacizumab group. However, median overall survival for the palliative intent cohort was significantly improved in the EGFRi group compared to bevacizumab group (53.2 vs 30.0 months; HR 0.70 [0.52 – 0.95]). When sequencing agents at progression, second-line PFS trended longer for those receiving EGFRi then bevacizumab, as compared to those receiving bevacizumab then EGFRi (7.9 vs 6.0 months; p=0.25). In this community series, first-line EGFRi plus doublet chemotherapy significantly improved OS when compared with bevacizumab plus doublet chemotherapy for left-side RAS wildtype mCRC patients. This was despite not demonstrating a PFS benefit in first-line, suggesting treatment sequencing may impact biologic efficacy. Despite EGFRi use increasing over time, 1 in 5 patients with left-side RAS wildtype mCRC never received any biologic agent.

Abstract A022: Effects of chemotherapy on the peripheral immune-cellome in patients with pancreatic cancer

Abstract Pancreatic cancer (PC) has become one of the leading causes of cancer related deaths. Late detection and resistance to therapy are two reasons for the dismal prognosis of this disease. Hence, there is an immense need for novel treatment options as well as predictive biomarkers, to prolong the life of these patients. The Chemotherapy, Host Response and Molecular Dynamics in Periampullary Cancer, the CHAMP study (clinical trial nr NCT03724994), is an ongoing observational, prospective clinical study that includes newly diagnosed patients with PC or other periampullary cancers receiving adjuvant or first-line palliative chemotherapy. The present study aims to investigate the peripheral immune-cellome in serial blood samples obtained during treatment from 24 patients, of whom 8 had resectable tumors. Buffy coat was isolated from blood samples taken at baseline (before treatment), after one month and after three to four months of treatment. Flow cytometry with two panels of antibodies was applied to detect major immune populations in both the innate and the adaptive immune system, as well as subpopulations of T cells. Immune cell frequencies were compared between patients with progression and no progression during treatment, and the associations of different immune cell subsets with overall survival were examined. As B cells have been highlighted as being of particular clinical relevance, single-cell transcriptomics and proteomics will be applied to further delineate the dynamics and prognostic impact of individual subtypes within this lineage. The results will provide important real-world data on the longitudinal dynamics of circulating immune cells under the pressure of chemotherapy in patients with PC. These results will in the future be related to analyses of circulating tumor DNA in matched blood samples, and together they will provide a foundation for forthcoming adaptive treatment trials based on results from the CHAMP study. Citation Format: Maja Svensson, Alexandra Petersson, Viktor Sincic, Sofie Olsson Hau, Jakob Eberhard, David Gisselsson Nord, Karin Leandersson, Kristina Lundberg, Karin Jirström. Effects of chemotherapy on the peripheral immune-cellome in patients with pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr A022.

Age-related Differences in Recall of Information and Handling of Chemotherapy-related Side Effects in Cancer Patients: The ReCap Study.

BackgroundTo prevent severe toxicity and hospital admissions, adequate management and recall of information about side effects are crucial and health literacy plays an important role. If age-related factors impact recall of given information and handling of side effects, revised ways to give information are required.Patients and MethodsWe undertook a questionnaire-based survey among 188 newly diagnosed patients with pancreatic cancer or colorectal cancer and chemo-naive patients with prostate cancer treated with adjuvant or first-line palliative chemotherapy comprising satisfaction with given information, recall of potential side effects, and handling of hypothetical side effect scenarios. We evaluated the association between baseline characteristics, ie, age, frailty (G8 score), comorbidity (Charlson Comorbidity Index), cognitive function (Mini-Cog), satisfaction, recall of information, and handling of side effects.ResultsReduced ability to recall information about several side effects (eg, chest pain) was associated with older age (odds ratio adjusted for cancer [aOR] 0.94 [95% CI, 0.88-0.98]) and poor cognitive screening (aOR 0.56 [95% CI, 0.33-0.91]). Insufficient or dangerous handling of side effects was associated with older age (aOR 0.96 (95% CI, 0.92-0.99)) and cognitive impairment (aOR 0.70 [95% CI, 0.50-0.95]).ConclusionOlder age and poor cognitive screening may impact patients’ ability to understand and adequately handle chemotherapy-related side effects. Cognitive screening and focus on individual ways to give information including assessment of recall and handling are needed.

Longitudinal monitoring of circulating tumor DNA (ctDNA) during disease course of metastatic colorectal cancer (mCRC).

189 Background: ctDNA is an attractive alternative to tissue for its easy accessibility and real time representation of systemic tumor profile. We explored the utility of ctDNA profiling during the course of mCRC treatment. Methods: Serial blood samples were obtained from mCRC patients before and during first-line palliative chemotherapy at fixed intervals (after every four cycles) until confirmed disease progression. ctDNA was sequenced using targeted next-generation sequencing (NGS) platform with 106 genes. Changes of ctDNA profile and treatment outcome were comprehensively analyzed. Results: A total of 272 samples from 62 patients were analyzed. In the pre-treatment blood samples, 56 (90.3%) of patients had detectable ctDNA mutations including single nucleotide variants, short insertions/deletions and copy number changes (median 4.5 mutations/ patient, range 0 - 133). In 31 (50.0%) patients who had tissue NGS panel results performed in the clinic, overall concordance between mutations from ctDNA and tissue was 86.5%. In three patients, ctDNA mutational profiles were found to be completely different from tissue profiles. At further investigation, these patients were found to have a separate primary cancer in their colon. At the time of the first follow-up, most (98.0%) patients showed decrease of ctDNA from baseline, represented by average variant allele frequency (VAF) changes of all ctDNA mutations found. Clearance of ctDNA was achieved in 40 (78.4%) patients and was associated with longer progression-free survival (median PFS 11.8 moths in ctDNA clearance (+) vs. 4.7 months in ctDNA clearance (-), p &lt; 0.001). The ctDNA clearance at the same time point was able to further discriminate the patients in same category by RECIST 1.1. Serial follow-up monitoring revealed three patterns of ctDNA changes at the time of clinical progressive disease (PD): 1) re-emergence or re-increase of baseline ctDNA mutations, 2) emergence of new resistance mutations, 3) radiologic PD without evidence of ctDNA progression. In the patients with detectable ctDNA at PD, the ctDNA progression preceded radiologic progression in 25 (58.1%) patients by median of 3.3 months. The patients in clinical PD without ctDNA progression showed different patterns of metastasis having mainly extrahepatic spread, while 77.8% of the patients with ctDNA progression had their progression confirmed in liver metastasis. Diverse resistant mutations and gene amplifications in PD patients were discovered by ctDNA sequencing. For seven (16.3%) of the PD patients, the newly identified mutations could be potential candidates of targeted therapy or clinical trial. Conclusions: ctDNA profile provided additional information to conventional evaluation methods and reflected dynamic changes. ctDNA monitoring may improve precise treatment decision-making for individual patients.

Predictive factors for renal function deterioration during palliative first-line chemotherapy for metastatic colorectal cancer.

85 Background: Effective first-line therapy is a key determinant of treatment outcomes and should be selected after considering both clinical factors and biological markers in metastatic colorectal cancer (mCRC). Considering the increased number of cancer patients with old age and their chronic diseases, it is essential to select a therapeutic agent by evaluating the toxicity that may occur due to long-term chemotherapy. This study assessed changes in renal function for 1 year in patients diagnosed with mCRC during chemotherapy and analyzed the factors and effect of each chemotherapy regimen on renal function. Methods: We retrospectively investigated patients with mCRC treated with palliative 1st line chemotherapy at our institution from 2015 to 2020. According to the common 1st line treatment regimen, we divided into 4 groups; FOLFOX/FOLFIRI with bevacizumab/cetuximab. We checked the baseline renal function and 3, 6, 9 and 12 months after the start of chemotherapy. The change in estimated glomerular filtration rate (△eGFR) was calculated as [(eGFR at each time point) - (eGFR at baseline)/(eGFR at baseline) X 100]. The clinical factors such as age, gender, chronic disease, BMI (body mass index), disease status, baseline proteinuria, and 1st line chemotherapy regimen were evaluated. Proteinuria was detected on urine dipstick protein ≥ 1+. Additionally, predictors for ΔeGFR ≤ −30% at each time points after therapy initiation were evaluated using multivariate logistic regression analysis. Results: Among 466 mCRC patients, the median eGFR values at baseline was 95.4 ml/min/1.73m2. The median eGFR at 6 months after chemotherapy initiation were significantly lower than baseline (88.3 ml/min/1.73m2, p &lt; 0.001). As 1 year, patients with more than 30% worsening of renal function was observed in 27.6 % in FOLFIRI + bevacizumab, 26.3 % in FOLFOX + bevacizumab, 6.6 % in FOLFIRI + cetuximab, and 4.7 % in FOLFOX + cetuximab group. The FOLFIRI + bevacizumab was an independent predictor for ΔeGFR ≤ −30% at 6 months (odds ratio (OR) 1.94, 95% confidence interval (CI) 1.05-3.47, p = 0.034) along with old age (≥ 65 years, OR 2.18, 95% CI 1.29-3.68, p = 0.004) and BMI (p = 0.012). Additionally, FOLFIRI + bevacizumab regimen causes more proteinuria (46.4%) than other chemotherapy regimens. Conclusions: Deterioration of renal function was more common with FOLFIRI + bevacizumab than other combination regimen. Old age, BMI were also associated decreasing eGFR. These results will be helpful to be suggested as important consideration when selecting the 1st line chemotherapy regimen for mCRC.

Impact of mismatch repair or microsatellite status on the prognosis and efficacy to chemotherapy in metastatic colorectal cancer patients: A bi-institutional, propensity score-matched study.

Background: Deficient mismatch repair (dMMR) or the microsatellite instability (MSI) phenotype occupied approximately 15-18% of CRC patients. Previous studies showed that dMMR/MSI status is a favorable prognostic factor for stage II/III CRC patients. For metastatic colorectal cancer (mCRC) patients, only 5% of patients have the dMMR/MSI-H phenotype. The relationship between dMMR/MSI, chemosensitivity and survival in mCRC patients of real-world is still not clear.Materials and methods: In this study, we enrolled 77 dMMR/MSI-H mCRC patients and compared their clinicopathological characteristics with those of 510 proficient MMR (pMMR) or microsatellite stable (MSS) mCRC patients. With propensity score matching (PSM) analysis, we further compared the chemosensitivity and survival of dMMR/MSI-H mCRC patients with pMMR/MSS patients. We also analyzed the efficacy of different chemotherapy and target therapy in the dMMR/MSI-H population.Results: In PSM cohort, the objective response rate (ORR) of mCRC patients with dMMR/MSI-H undergoing first-line palliative chemotherapy was 35.2%, which was similar with patients with pMMR/MSS (35.4%, p = 1.00). The median progression-free survival (PFS) of first-line chemotherapy was significantly different (dMMR/MSI-H vs pMMR/MSS = 7.4 months vs 10.2 months; HR = 0.74; 95%CI, 0.57-0.98; p = 0.03). Overall survival (OS) of patients did not significantly differ by status (dMMR/MSI-H vs pMMR/MSS = 40.0 months vs 41.3 months; HR = 1.09; 95%CI, 0.74-1.59; p = 0.68). For second-line palliative chemotherapy, there was no difference in ORR (p = 0.53) or in PFS (HR = 0.88; 95%CI, 0.59-1.33; p = 0.56) between dMMR/MSI-H and pMMR/MSS tumors. We also found that in the overall cohort, the ORR of patients who received oxaliplatin-based and irinotecan-based chemotherapy were 28.8% and 54.5%, respectively, which were not significantly different (p = 0.16). Our results also showed that the use of bevacizumab could lead to a significantly higher ORR in dMMR/MSI-H mCRC patients compared to chemotherapy alone (55.0% vs 22.2%; p = 0.02), whereas cetuximab could not.Conclusion: The dMMR/MSI-H is not a prognostic factor for mCRC patients but is correlated with shorter PFS to first-line palliative chemotherapy.

Information provision to older patients receiving palliative chemotherapy: a quality study

ObjectivesCancer treatment has become increasingly successful. However, prolonging and preserving life has become an important goal of therapy since many patients generally receive palliative chemotherapy. The perception of life changes...

Frailty and treatment outcome in advanced gastro-oesophageal cancer: An exploratory analysis of the GO2 trial

IntroductionResearch into the optimal management of frail patients with cancer is limited and treatment decision-making in this cohort can be difficult. A number of measures have been developed to assess frailty, but few studies explore the correlation between frailty measures and cancer treatment outcomes. MethodsThis retrospective cohort study is an exploratory analysis of the GO2 randomised controlled trial. GO2 recruited both older and frail younger patients commencing first-line palliative chemotherapy for advanced gastro-oesophageal (aGO) cancer. This analysis aims to explore the correlation between baseline frailty and treatment outcome. Baseline frailty measures were derived from clinical data and included ECOG Performance Status (PS), the GO2 Frailty Score (GO2FS), Geriatric-8 (G8), Cancer and Aging Research Group (CARG) toxicity score and a ‘modified’ Rockwood Clinical Frailty Scale (mCFS). Novel patient-centred composite measure Overall Treatment Utility (OTU) was the primary endpoint. Ordinal logistic regression was undertaken to give odds ratios for poor vs good/intermediate OTU. Secondary endpoints were progression-free and overall survival. Models were adjusted for age, sex, histology, metastases, Trastuzumab and renal/hepatic function. ResultsIn GO2, 514 patients were randomised between three chemotherapy dose-levels; all of these patients were assessed for OTU and are included in this analysis. Worse GO2FS, mCFS and G8 scores all had a statistically significant association with poor (vs good/intermediate) OTU, progression and death, which persisted after adjustment. Adjusted odds ratios for poor OTU amongst those with the worst GO2FS and mCFS and best G8 scores were as follows: 1.85 (95% confidence interval [CI] 1.20–2.88) for GO2FS ≥3 (‘severely frail’), 1.72 (1.19–2.50) for mCFS 5+ (‘frail’) and 0.57 (0.32–1.00) for G8 > 14 (‘normal’). Worse ECOG PS and CARG scores did not have a statistically significant association with poor OTU/progression/death. ConclusionIn this study, frailty identified via GO2FS, mCFS and G8 conveyed a statistically significant increased risk of worse treatment outcome in older and frail younger patients with aGO cancer. Frailty assessment provides information over and above PS and should be integrated alongside routine assessments in research and clinical practice. In the absence of prospective data, frailty measures can be derived retrospectively to build the evidence base around optimal care of frailer patients.

2021 Canadian Surgery Forum: Virtual, online Sept. 21-24, 2021.

# 01. Design and validation of a unique endoscopy simulator using a commercial video game {#article-title-2} Procedural simulation has been shown to enhance early endoscopy training. In this proof of concept study, we aimed to show that a first-person shooter (FPS) video game with a novel in-house

Treatment Patterns, Toxicity, and Outcomes of Older Adults With Advanced Pancreatic Cancer Receiving First-line Palliative Chemotherapy.

Advanced pancreatic cancer (APC) disproportionately impacts older adults. Randomized trials demonstrate improved overall survival (OS) with combination chemotherapy including 5-fluorouracil, irinotecan, leucovorin, and oxaliplatin (FOLFIRINOX) or nab-paclitaxel and gemcitabine compared with gemcitabine alone, but with increased toxicity. Older adults are at increased risk of side effects from chemotherapy. The aim of this study was to assess the efficacy and toxicity of chemotherapy in older adults with APC. Patients diagnosed with APC from 2011 to 2016 were identified using the Manitoba Cancer Registry. Patient and treatment characteristics, toxicity, and outcomes of patients 65 years of age and above treated with palliative chemotherapy were compared by treatment regimen. OS was assessed using the Kaplan-Meier method. A Cox regression was used to identify independent predictors of OS. A total of 87 patients aged 65 years and above received palliative chemotherapy: 52 (59.7%) FOLFIRINOX, 21 (24.1%) nab-paclitaxel and gemcitabine, and 14 (16.1%) gemcitabine, with a median age of 69 (65 to 84), 75 (65 to 88), and 73 (67 to 82), Eastern Cooperative Oncology Group (ECOG) performance status difference in hematologic toxicity between regimens (P=0.807). An increase in nonhematologic toxicity was seen with FOLFIRINOX (P<0.001), specifically neuropathy (P=0.008), fatigue (P<0.001), and nausea/vomiting (P=0.008). FOLFIRINOX was associated with improved radiologic response (P=0.05) and OS (P=0.035). PS, baseline carbohydrate antigen 19-9 level, and chemotherapy regimen were independent predictors of survival. FOLFIRINOX is associated with improved response and OS in older adults with APC. FOLFIRINOX has a manageable safety profile in this population and should be considered in fit older adults with APC.

Prevalence of BRCA1 and BRCA2 pathogenic sequence variants in ovarian cancer patients in the Gulf region: the PREDICT study

BackgroundPatients with pathogenic sequence variants (PSVs) in BRCA1/BRCA2 are at high risk of developing ovarian cancer (OC). However, genetic testing for BRCA1/BRCA2 PSVs is still not a routine practice in the Middle East. With the lack of epidemiological studies in the region, we aim to describe the prevalence of BRCA1/BRCA2 PSVs in patients with OC across different countries in the Gulf region.MethodsThe PREDICT study was an observational, prospective, epidemiological study, which consecutively recruited women with ovarian, primary peritoneal, and fallopian tube cancers from the following Gulf countries over the period from July 2017 to July 2019; United Arab Emirates (UAE), Kuwait, and Oman. The study was approved by the local ethics committee of participating centers. The BRCA1/BRCA2 PSVs were assessed by tissue genetic testing using next-generation sequencing (NGS).ResultsA total of 105 women were included with a median age at diagnosis of 52 years (IQR 44.5 – 61.0). Nearly 11.4% of patients reported a family history of ovarian or breast cancer, while 4.7% of patients reported a family history of other cancers. Most of the patients (70.3%) had advanced disease (FIGO stage III/IV) at presentation. Eighty-eight patients (84%) were successfully tested for somatic BRCA1/BRCA2 PSVs. Fifteen patients (17%) were found to have PSVs in either BRCA1, BRCA2, or both genes; of them, 10 patients (11.2%) had BRCA1 somatic PSVs alone, eight patients (9.1%) had BRCA2 somatic PSVs, while three patients (2.9%) had both PSVs. Five patients with BRCA1/BRCA2 somatic PSVs had germline PSVs tests, and three of them tested positive. Concerning treatment, 87.6% of patients received perioperative chemotherapy and 6.6% as first-line palliative chemotherapy. Eighty-seven (82.9%) patients underwent debulking surgery, with no residual disease in 42.5% of patients.ConclusionOur study showed that the prevalence of BRCA1/BRCA2 somatic PSVs in patients with OC is higher than the reported global figures (2-8%). However, more studies are warranted to further elucidate the prevalence of BRCA1/BRCA2 somatic and germline PSVs, as well as other relevant genetic alterations, to better understand their impact on OC patient outcomes in Gulf countries.Trial registrationNCT03082976.

Amphiregulin can predict treatment resistance to palliative first-line cetuximab plus FOLFIRI chemotherapy in patients with RAS wild-type metastatic colorectal cancer

Amphiregulin (AREG) is an epidermal growth factor receptor (EGFR) ligand. The aim of this study was to investigate the effects of baseline plasma AREG levels in KRAS, NRAS, and BRAF wild-type metastatic colorectal cancer (CRC) on treatment outcome with palliative first-line cetuximab + FOLFIRI chemotherapy. Chemotherapy outcomes were analyzed based on baseline plasma AREG levels. The clinical findings were further validated using an in vitro model of CRC. Among 35 patients, the progression-free survival (PFS) was significantly inferior in patients with high AREG than in those with low AREG levels: 10.9 vs. 24.2 months, respectively (p = 0.008). However, after failure of first-line chemotherapy, AREG levels were associated with neither PFS (4.8 vs. 11.6 months; p = 0.215) nor overall survival (8.4 vs. 13.3 months; p = 0.975). In SNU-C4 and Caco-2 cells which were relatively sensitive to cetuximab among the seven CRC cell lines tested, AREG significantly decreased the anti-proliferative effect of cetuximab (p < 0.05) via AKT and ERK activation. However, after acquiring cetuximab resistance with gradual exposure for more than 6 months, AREG neither increased colony formation nor activated AKT and ERK after cetuximab treatment. Our results suggest that plasma AREG is a potential biomarker to predict clinical outcomes after cetuximab-based chemotherapy.

Cetuximab resistance induced by hepatocyte growth factor is overcome by MET inhibition in KRAS, NRAS, and BRAF wild-type colorectal cancers.

Recent evidence has highlighted the role of hepatocyte growth factor (HGF) as a putative biomarker to predict EGFR inhibitor resistance. This study investigated the impact of plasma HGF levels on EGFR inhibition and the counter effect of MET inhibition in KRAS, NRAS, and BRAF (RAS/RAF) wild-type colorectal cancers (CRCs). Plasma HGF levels were analyzed with clinical outcomes of patients with metastatic CRC (mCRC) receiving palliative first-line chemotherapy. Then, in vitro experiments were conducted to validate the clinical findings and to establish pre-clinical evidence of MET inhibition by capmatinib. A total of 80 patients were included: cetuximab + FOLFIRI (n = 35) and bevacizumab + FOLFIRI (n = 45). Both progression-free survival (PFS) and overall survival (OS) were significantly lesser in the high vs low HGF group: median 11.8 vs. 24.7months, respectively, for PFS (p = 0.009), and median 21.1months vs. not reached, respectively, for OS (p = 0.018). The difference was significantly evident in the cetuximab group. In five RAS/RAF wild-type CRC cells, the addition of HGF activated ERK1/2 and AKT via MET phosphorylation, resulting in cetuximab resistance in vitro. In cetuximab-sensitive Caco-2 and SNU-C4 cells, capmatinib overcame cetuximab resistance in the presence of HGF by attenuating HGF-induced MET signaling activation. Patients with mCRC receiving cetuximab + FOLFIRI who presented with high plasma HGF levels had significantly worse PFS and OS. Cetuximab resistance induced by HGF was mediated by AKT and ERK activation and overcome by MET inhibition in vitro.

Real-World Data from a Refractory Triple-Negative Breast Cancer Cohort Selected Using a Clinical Data Warehouse Approach.

Simple SummaryPatients with metastatic triple-negative breast cancer (mTNBC) have a very poor prognosis. We assume that some mTNBC patients have worse treatment outcomes and defined them as cases of refractory TNBC. We tried to investigate the characteristics and treatment outcomes of our refractory mTNBC cohort selected using a clinical data warehouse (CDW) approach. Between January 1997 and December 2019, TNBC patients were searched for in the breast cancer registry and, among them, pathologically confirmed mTNBC patients were selected as the study cohort (n = 451). Refractory TNBC was defined as cases of TNBC with confirmed distant metastasis within one year after adjuvant treatment. The refractory mTNBC group was younger and had a higher proportion of Ki-67 ≥ 3+ than the nonrefractory group. In addition, a much poorer prognosis existed among mTNBC patients, with an overall survival (OS) of 14.3 months and progression-free survival (PFS) of 4.2 months after first-line palliative chemotherapy compared to an OS of 24.8 months and PFS of 6.2 months in the nonrefractory TNBC group (p < 0.001).Purpose: Triple-negative breast cancer (TNBC) is well known for its aggressive course and poor prognosis. In this study, we sought to investigate clinical, demographic, and pathologic characteristics and treatment outcomes of patients with refractory, metastatic TNBC selected by a clinical data warehouse (CDW) approach. Patients and methods: Data were extracted from the real-time breast cancer registry integrated into the Data Analytics and Research Window for Integrated Knowledge C (DARWIN-C), the CDW of Samsung Medical Center. Between January 1997 and December 2019, a TNBC cohort was searched for in the breast cancer registry, which includes records from more than 40,000 patients. Among them, cases of pathologically confirmed metastatic TNBC (mTNBC) were selected as the cohort group (n = 451). The extracted data from the registry via the CDW platform included clinical, pathological, laboratory, and chemotherapy information. Refractory TNBC was defined as confirmed distant metastasis within one year after adjuvant treatment. Results: This study comprised a total of 451 patients with mTNBC, including 69 patients with de novo mTNBC, 131 patients in the nonrefractory TNBC group with confirmed stage IV disease after one year of adjuvant treatment, and 251 patients with refractory mTNBC, whose disease recurred as stage IV within one year after completing adjuvant treatment. The refractory mTNBC cohort was composed of patients with disease that recurred at stage IV after surgery (refractory mTNBC after surgery) (n = 207) and patients in whom metastasis was confirmed during neoadjuvant chemotherapy (unresectable TNBC due to progression during neoadjuvant chemotherapy) (n = 44). Patients in the refractory mTNBC group were younger than those in the nonrefractory group (median age 46 vs. 51 years; p < 0.001). Considering the pathological findings, the refractory group had a greater proportion of cases with Ki-67 ≥ 3+ than did the nonrefractory group (71% vs. 47%; p = 0.004). During a median 8.4 years of follow-up, the overall survival was 24.8 months in the nonrefractory mTNBC group and 14.3 months in the refractory mTNBC group (p < 0.001), and the median progression-free survival periods were 6.2 months and 4.2 months, respectively (p < 0.001). The median disease-free survival period was 30.1 months in the nonrefractory mTNBC group and only 7.6 months in the refractory mTNBC group. Factors related to metastatic sites affecting overall survival were liver metastasis at diagnosis (p < 0.001) and leptomeningeal involvement (p = 0.001). Conclusions: We revealed that patients with refractory mTNBC had a much poorer prognosis among all mTNBC cases and described the characteristics of this patient group.

The Association of Drug-Funding Reimbursement With Survival Outcomes and Use of New Systemic Therapies Among Patients With Advanced Pancreatic Cancer

Gemcitabine-nab-paclitaxel (GEMNAB) and fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) both improve survival of patients with advanced pancreatic cancer when compared with single-agent gemcitabine in clinical trials. To describe changes in the survival of patients with advanced pancreatic cancer associated with sequential drug-funding approvals and to determine if there exist distinct patient populations for whom GEMNAB and FOLFIRINOX are associated with survival benefit. This population-based, retrospective cohort study examined all incident cases of advanced pancreatic cancer treated with first-line chemotherapy in Ontario, Canada (2008-2018) that were identified from the Cancer Care Ontario (Ontario Health) New Drug Funding Program database. Statistical analysis was performed from October 2020 to January 2021. First-line chemotherapy for advanced pancreatic cancer. The main outcomes were the proportion of patients treated with each chemotherapy regimen over time and overall survival for each regimen. Cox proportional hazards regression models were used to compare overall survival between treatment regimens after adjustment for confounding variables, inverse probability of treatment weighting, and matching. From 2008 to 2018, 5465 patients with advanced pancreatic cancer were treated with first-line chemotherapy in Ontario, Canada. The median (range) age of patients was 66.9 (27.8-93.4) years; 2447 (45%) were female; 878 (16%) had prior pancreatic resection, and 328 (6%) had prior adjuvant gemcitabine. During the time period when only gemcitabine and FOLFIRINOX were funded (2011-2015), 49% (929 of 1887) received FOLFIRINOX. When GEMNAB was subsequently funded (2015-2018), 9% (206 of 2347) received gemcitabine, 44% (1034 of 2347) received FOLFIRINOX, and 47% (1107 of 2347) received GEMNAB. The median overall survival increased from 5.6 months (95% CI, 5.1-6.0 months) in 2008 to 2011 to 6.9 months (95% CI, 6.5-7.4 months) in 2011 to 2015 to 7.6 months (95% CI, 7.1-8.0 months) in 2015 to 2018. Patients receiving FOLFIRINOX were younger and healthier than patients receiving GEMNAB. After adjustment and weighting, FOLFIRINOX was associated with better overall survival than GEMNAB (hazard ratio [HR], 0.75 [95% CI, 0.69-0.81]). In analyses comparing patients treated with GEMNAB and gemcitabine, GEMNAB was associated with better overall survival (HR, 0.86 [95% CI, 0.78-0.94]). This cohort study of patients with advanced pancreatic cancer receiving first-line palliative chemotherapy within a universal health care system found that drug funding decisions were associated with increased uptake of new treatment options over time and improved survival. Both FOLFIRINOX and GEMNAB were associated with survival benefits in distinct patient populations.

Impact of skeletal muscle mass in patients with unresectable gastric cancer who received palliative first-line chemotherapy based on 5-fluorouracil

BackgroundThe mortality rate of patients with unresectable gastric cancer (UGC) has decreased with the development of chemotherapies and surgical techniques. However, the survival rate remains low. We retrospectively examined the prognostic significance of the pretreatment skeletal muscle mass index (SMI) and nutritional and inflammatory factors in patients with UGC.MethodsThis study included 83 patients diagnosed with UGC at Tottori University Hospital who received palliative chemotherapy based on 5-fluorouracil. Pretreatment computed tomography (CT) measured overall skeletal muscle mass (SMM) and cross-sectional SMM at the third lumbar vertebra (L3). We focused on the neutrophil-to-lymphocyte ratio (NLR), C-reactive protein-to-albumin ratio (CAR), prognostic nutritional index (PNI), and platelet-to-lymphocyte ratio (PLR) as nutritional and inflammatory factors.ResultsReceiver operating characteristic curve analysis was performed for median survival time (MST) after palliative chemotherapy. SMIs for males and females (43.9 cm2/m2 and 34.7 cm2/m2, respectively) were the cutoff values, and patients were divided into high (SMIHigh; n = 41) and low SMI groups (SMILow; n = 42). Body mass index (BMI) was significantly higher in patients in the SMIHigh group than in the SMILow group (p < 0.001). The number of patients who received third-line chemotherapy was significantly higher in the SMIHigh group than in the SMILow group (p = 0.037). The MST was significantly higher in the SMIHigh group than in the SMILow group (17.3 vs. 13.8 months; p = 0.008). The incidence of grade 3 or 4 side effects was significantly higher in patients with SMILow UGC (p = 0.028). NLR was significantly higher in patients with SMILow than it was in those with SMIHigh. (p = 0.047). In the univariate analysis, performance status, SMI, histological type, lines of chemotherapy, and NLR were prognostic indicators. The multivariate analysis identified SMI (p = 0.037), NLR (p = 0.002), and lines of chemotherapy (p < 0.001) as independent prognostic factors.ConclusionsThe SMILow group had significantly more grade 3 or 4 side effects, were related to high NLR, and had a significantly worse prognosis than the SMIHigh group.Trial registrationRetrospectively registerd.

Management of first‐line palliative chemotherapy for post‐treatment metastasis after gemcitabine plus cisplatin induction chemotherapy: Gemcitabine plus cisplatin and non‐gemcitabine plus cisplatin chemotherapy

To evaluate whether patients with post-treatment metastasis are suitable for GP first-line palliative chemotherapy (PCT) after undergoing GP IC. Seven hundred and forty-six patients with post-treatment metastasis after undergoing GP IC were eligible. Survival outcomes were compared. Significant differences in survival rates were observed between patients treated with GP and non-GP chemotherapy (2-year progression-free survival [PFS]: 0.7% vs. 9.7%). We investigated survival outcomes of patients treated with GP PCT within 2 years after undergoing GP IC, treated with GP PCT 2 years after undergoing GP IC, and those of non-GP PCT patients (2-year PFS: 0.0%, 2.3%, 9.7%). However, there was no difference in the 2-year PFS between the patients that received GP PCT 2 years after undergoing GP IC and the non-GP PCT treated patients. GP is not recommended for patients that have received GP IC within 2 years. Two years after undergoing GP IC, GP can be considered.

First-Line Palliative Chemotherapy for Esophageal and Gastric Cancer: Practice Patterns and Outcomes in the General Population.

Clinical trials have shown that palliative chemotherapy (PC) improves survival in patients with incurable esophageal and gastric cancer; however, outcomes achieved in routine practice are unknown. We describe treatment patterns and outcomes among patients treated in the general population of Ontario, Canada. The Ontario Cancer Registry was used to identify patients with esophageal or gastric cancer from 2007 to 2016, and data were linked to other health administrative databases. Patients who received curative-intent surgery or radiotherapy were excluded. Factors associated with the receipt of PC were determined using logistic regression. First-line PC regimens were categorized, and trends over time were reported. Survival was determined using the Kaplan-Meier method. The cohort included 9,848 patients; 22% (2,207 of 9,848) received PC. Patients receiving PC were younger (mean age, 63 v 74 years; P < .0001) and more likely male (71% v 65%; P < .0001). Thirty-seven percent of non-PC patients saw a medical oncologist in consultation. Over the study period, utilization of PC increased (from 11% in 2007 to 19% in 2016; P < .0001), whereas the proportion of patients receiving triplet regimens decreased (65% in 2007 to 56% in 2016; P = .04). In the PC group, the median overall and cancer-specific survival from treatment initiation was 7.2 months. One fifth of patients with incurable esophageal and gastric cancer in the general population receive PC. Median survival of patients treated in routine practice is inferior to that in clinical trials. Only one third of patients not treated with PC had consultation with a medical oncologist. Further work is necessary to understand low utilization of PC and medical oncology consultation in this patient population.

First-line palliative chemotherapy clinical benefit is a key determinant of survival in metastatic uterine leiomyosarcoma

Aim: To evaluate whether obtaining a clinical benefit with first-line therapy in patients receiving palliative systemic therapy with a diagnosis of metastatic uterine leiomyosarcoma (ULMS) provides a survival benefit and the factors that may predict first-line therapy response.&#x0D; Material and Method: This study was a retrospective observational single-center analysis conducted with patients diagnosed with metastatic ULMS. Patients who received palliative chemotherapy with an ECOG PS of 0 or 1 at the time of diagnosis of metastatic disease were included in the study. Main patient characteristics, first-line palliative treatment responses, progression-free survival, and overall survival (OS) were reviewed retrospectively. Multivariate analyses were performed to determine the independent predictive factors of first-line palliative treatment response and overall survival.&#x0D; Results: Of the 36 patients whose medical records were evaluated retrospectively, 24 patients who were eligible for the study were included in the study. Gemcitabine plus docetaxel combination chemotherapy was the most commonly used treatment protocol (n=12, 50%) for first-line palliative treatment. While a complete response as a first-line treatment response could not be achieved, clinical benefit (partial remission and stable disease) and progressive disease were observed in 15 (62%) and 9 (37.5%) patients, respectively. Binary logistic regression analysis failed to detect any independent predictive factors for the clinical benefit of first-line palliative therapy. Median (OS) was 19.7 (95% CI, 4.1-35.3) months for all patients (N=24). Median OS was 25.6 (95% CI, 21.0-30.2) months and 6.9 (95% CI, 1.7-12.2) months for patients with and without the clinical benefit of first-line palliative chemotherapy (p=0.004). Cox-regression analysis revealed that increasing age at diagnosis of metastatic disease (HR=0.929, 95% CI 0.870-0.992, p=0.027), pulmonary metastasectomy (HR=0.162, 95%CI 0.031-0.863, p=0.033), and presence of first-line palliative chemotherapy clinical benefit (HR=0.195, 95% CI 0.063-0.606, p=0.005) were independent predictive factors for a better OS.&#x0D; Conclusion: In metastatic ULMS, for which the survival benefit is not clear with palliative chemotherapy, prolonged survival can be obtained in patients with clinical benefit with first-line palliative chemotherapy. There is a need for new studies to determine the factors that will predict the clinical benefit of first-line palliative chemotherapy.