Probiotic Supplementation Attenuates Chemotherapy-Induced Intestinal Mucositis in an Experimental Colorectal Cancer Liver Metastasis Rat Model.

The use of chemotherapeutic agents is of paramount importance when treating colorectal cancer (CRC). Unfortunately, one of the most frequent chemotherapy (CTx) side effects is intestinal mucositis (IM), which may present with several clinical symptoms such as nausea, bloating, vomiting, pain, and diarrhea and even can result in life-threatening complications. There is a focused scientific effort towards developing new therapies to prevent and treat IM. The aim of this study was to assess the outcomes of probiotic supplementation on CTx-induced IM in a CRC liver metastasis rat model. Six-week-old male Wistar rats received either a multispecies probiotic or placebo mixture. On the 28th experiment day, rats received FOLFOX CTx, and afterwards, the severity of diarrhea was evaluated twice daily. Stool samples were collected for further microbiome analysis. Additionally, immunohistochemical stainings of ileum and colon samples with were performed with MPO, Ki67, and Caspase-3 antibodies. Probiotic supplementation alleviates the severity and length of CTx-induced diarrhea. Additionally, probiotics significantly reduced FOLFOX-induced weight and blood albumin loss. Furthermore, probiotic supplementation mitigated CTx-induced histological changes in the gut and promoted intestinal cell regeneration. This study shows that multispecies probiotic supplementation attenuates FOLFOX-induced IM symptoms by inhibiting apoptosis and promoting intestinal cell proliferation.

Adagrasib with or without Cetuximab in Colorectal Cancer with Mutated KRAS G12C.

BACKGROUND: Adagrasib, an oral small-molecule inhibitor of mutant KRAS G12C protein, has shown clinical activity in pretreated patients with several tumor types, including colorectal cancer. Preclinical studies suggest that combining a KRAS G12C inhibitor with an epidermal growth factor receptor antibody could be an effective clinical strategy. METHODS: In this phase 1-2, open-label, nonrandomized clinical trial, we assigned heavily pretreated patients with metastatic colorectal cancer with mutant KRAS G12C to receive adagrasib monotherapy (600 mg orally twice daily) or adagrasib (at the same dose) in combination with intravenous cetuximab once a week (with an initial loading dose of 400 mg per square meter of body-surface area, followed by a dose of 250 mg per square meter) or every 2 weeks (with a dose of 500 mg per square meter). The primary end points were objective response (complete or partial response) and safety. RESULTS: As of June 16, 2022, a total of 44 patients had received adagrasib, and 32 had received combination therapy with adagrasib and cetuximab, with a median follow-up of 20.1 months and 17.5 months, respectively. In the monotherapy group (43 evaluable patients), a response was reported in 19% of the patients (95% confidence interval [CI], 8 to 33). The median response duration was 4.3 months (95% CI, 2.3 to 8.3), and the median progression-free survival was 5.6 months (95% CI, 4.1 to 8.3). In the combination-therapy group (28 evaluable patients), the response was 46% (95% CI, 28 to 66). The median response duration was 7.6 months (95% CI, 5.7 to not estimable), and the median progression-free survival was 6.9 months (95% CI, 5.4 to 8.1). The percentage of grade 3 or 4 treatment-related adverse events was 34% in the monotherapy group and 16% in the combination-therapy group. No grade 5 adverse events were observed. CONCLUSIONS: Adagrasib had antitumor activity in heavily pretreated patients with metastatic colorectal cancer with mutant KRAS G12C, both as oral monotherapy and in combination with cetuximab. The median response duration was more than 6 months in the combination-therapy group. Reversible adverse events were common in the two groups. (Funded by Mirati Therapeutics; KRYSTAL-1 ClinicalTrials.gov number, NCT03785249.).

Benefit from upfront FOLFOXIRI and bevacizumab in BRAFV600E-mutated metastatic colorectal cancer patients: does primary tumour location matter?

BACKGROUND: Recent data suggest that BRAFV600E-mutated metastatic colorectal cancer (mCRC) patients with right-sided tumours and ECOG-PS = 0 may achieve benefit from the triplet regimen differently than those with left-sided tumours and ECOG-PS > 0. METHODS: The predictive impact of primary sidedness and ECOG-PS was evaluated in a large real-life dataset of 296 BRAFV600E-mutated mCRC patients treated with upfront triplet or doublet ± bevacizumab. Biological differences between right- and left-sided BRAFV600E-mutated CRCs were further investigated in an independent cohort of 1162 samples. RESULTS: A significant interaction effect between primary sidedness and treatment intensity was reported in terms of both PFS (p = 0.010) and OS (p = 0.003), with a beneficial effect of the triplet in the right-sided group and a possible detrimental effect in the left-sided. No interaction effect was observed between ECOG-PS and chemo-backbone. In the MSS/pMMR population, a consistent trend for a side-related subgroup effect was observed when FOLFOXIRI ± bevacizumab was compared to oxaliplatin-based doublets±bevacizumab (p = 0.097 and 0.16 for PFS and OS, respectively). Among MSS/pMMR tumours, the BM1 subtype was more prevalent in the right-sided group (p = 0.0019, q = 0.0139). No significant differences were observed according to sidedness in the MSI-H/dMMR population. CONCLUSIONS: Real-life data support the use of FOLFOXIRI ± bevacizumab only in BRAFV600E-mutated mCRC patients with right-sided tumours.

Concurrent BRAFV600E and BRCA Mutations in MSS Metastatic Colorectal Cancer: Prevalence and Case Series of mCRC patients with prolonged OS.

BACKGROUND: BRAF V600E+ microsatellite stable (MSS) metastatic colorectal cancer (mCRC) patients comprise up to 10% of advanced CRC. They have a poor prognosis with a median survival typically <1 year. Despite use of multi-agent 1st line chemotherapy regimens and combination targeted therapies, outcomes are still poor. In our Institutional Molecular Tumor Board (MTB) database, we identified 3 mCRC patients with MSS/BRAF V600E who also had a BRCA1 or BRCA2 co-mutation and had relatively long overall survivals. Prior studies suggested that BRCA mutations are uncommon in CRC and we queried the Foundation Medicine (FM) genomic database to evaluate the prevalence of these cases as well as those with co-mutations in other homologous recombination genes. METHODS: 36,966 CRC pts were sequenced by FMI using hybrid capture comprehensive genomic profiling (CGP) to evaluate all classes of genomic alterations (GA) for pathogenic BRAF mutations and/or a mutation in BRCA1/2 or a co-mutation in other homologous recombination (HR) genes (BARD1, CDK12, FANCL, PALB2, ATM, RAD54L, CHEK2, BRAF, BRIP1, RAD51D, RAD51C, RAD51B, CHEK1). Selected cohort analysis of BRAF V600E co-mutated with BRCA1 and BRCA2 were separated into MSI-H and MSS cohorts. The clinicopathological features and genomic loss of heterozygosity (gLOH) of those with a BRAF V600E and a BRCA1/BRCA2 mutation were collected and analyzed. We also describe 3 consecutive cases of mCRC patients, identified through the Inova Schar Cancer Institute (ISCI) MTB registry, whom had prolonged OS. RESULTS: Of 36,966 colorectal cancer pts, 6.6% were BRAF V600E+ and 1.5% had any co-occurring HR gene mutation(s) with 0.6% of the total mCRC population having co-ocurring BRAF V600E and BRCA1/2 alterations. BRCA co-mutations were higher in MSI-High BRAF V600E, however 24.1% of co-occurrences were observed in MSS samples. BRCA1 co-mutation was more commonly associated with MSS BRAF V600E and was associated with a higher gLOH than MSI-H BRAF V600E (18.7% vs 2.8%; p <0.001). In our institutional MTB database, (3/241;1.2%) CRC patients were MSS, BRAF V600E+ with BRCA1 or BRCA2 co-mutations, all somatic in origin, with an average gLOH of 21.4% and overall survivals of 72+(alive), 17+(alive), and 30 months, respectively. CONCLUSION: Co-existence of BRAF V600E/BRCA1/2 may represent a unique subset of advanced MSS CRC that may have a better prognosis and represent an opportunity to test novel targeted therapies. The elevated gLOH in these cases may also be a valuable biomarker for these pts. Larger prospective clinical validation trials in this subset is warranted.

Disseminated epithelial cancers-An autopsy analysis.

BACKGROUND: Cancer is one of the leading causes of death due to noncommunicable diseases worldwide. Despite increasing public awareness and availability of sophisticated imaging techniques, some cancers evade clinical diagnosis and/or are incidentally encountered at autopsies, often with dissemination. AIMS: The present study evaluated the disseminated epithelial cancers at autopsy. MATERIALS AND METHODS: This is a retrospective observational 5-year autopsy analysis of disseminated epithelial cancers performed at a tertiary-care hospital. The cases were categorized as (1) clinically diagnosed malignancy, known primary; (2) clinically diagnosed malignancy, unknown primary; and (3) clinically undiagnosed malignancy. STATISTICAL ANALYSIS: Nil. RESULTS: Dissemination was identified in 66 (57.9%) of the 114 patients with epithelial malignancies. There were 29 patients (43.9%) in category 1, 26 patients (39.4%) in category 2, and 11 patients (16.7%) in category 3, majority of whom were women (38 patients, 57.6%). When all categories were considered together, lung and colorectal carcinomas were the commonest cancers seen in 13 (19.7%) and 8 (12.1%) patients, respectively, in both men and women. Majority of the patients (43 cases, 65.2%) had symptoms produced by metastases, which were the sole manifestations in 13 patients (19.7%). Lungs and liver were the common metastatic sites. CONCLUSIONS: Cancerous dissemination continues to be a major cause of morbidity and mortality even after considerable improvements in the surgical or nonsurgical treatment modalities. An autopsy study can provide important clinical insights in retrospect.

Survival after secondary liver resection in metastatic colorectal cancer: Comparing data of three prospective randomized European trials (LICC, CELIM, FIRE-3).

Metastatic colorectal cancer (mCRC) patients with liver-limited disease (LLD) have a chance of long-term survival and potential cure after hepatic metastasectomy. However, the appropriate postoperative treatment strategy is still controversial. The CELIM and FIRE-3 studies demonstrated that secondary hepatic resection significantly improved overall survival (OS). The objective of this analysis was to compare these favorable outcome data with recent results from the LICC trial investigating the antigen-specific cancer vaccine tecemotide (L-BLP25) as adjuvant therapy in mCRC patients with LLD after R0/R1 resection. Data from mCRC patients with LLD and secondary hepatic resection from each study were analyzed for efficacy outcomes based on patient characteristics, treatment and surveillance after surgery. In LICC, 40/121 (33%) patients, in CELIM 36/111 (32%) and in FIRE-3-LLD 29/133 (22%) patients were secondarily resected, respectively. Of those, 31 (77.5%) patients in LICC and all patients in CELIM were R0 resected. Median disease-free survival after resection was 8.9 months in LICC, 9.9 months in CELIM. Median OS in secondarily resected patients was 66.1 months in LICC, 53.9 months in CELIM and 56.2 months in FIRE-3-LLD. Median age was about 5 years less in LICC compared to CELIM and FIRE-3. Secondarily resected patients of LICC, CELIM and FIRE-3 showed an impressive median survival with a tendency for improved survival for patients in the LICC trial. A younger patient cohort but also more selective surgery, improved resection techniques, deep responses and a close surveillance program after surgery in the LICC trial may have had a positive impact on survival.

Lymphovascular Infiltration, Not Depth of Invasion, is the Critical Risk Factor of Metastases in Early Colorectal Cancer: Retrospective Population-based Cohort Study on Prospectively Collected Data, Including Validation.

OBJECTIVE: To identify clinical and histopathological risk factors of LNM in T1 CRC. SUMMARY OF BACKGROUND DATA: The requisite of additional surgery after locally resected T1 CRC is dependent on the risk of LNM. Depth of submucosal invasion is used as a key predictor of lymphatic metastases although data are conflicting on its actual impact. METHODS: Retrospective population-based cohort study on prospectively collected data on all patients with T1 CRC undergoing surgical resection in Sweden, 2009-2017 and Denmark 2016-2018. The Danish cohort was used for validation. Potential risk factors of LNM investigated were; age, sex, tumor location, submucosal invasion, grade of differentiation, mucinous subtype, lymphovascular, and perineural invasion. RESULTS: One hundred fifty out of the 1439 included patients (10%) had LNM. LVI (P < 0.001), perineural invasion (P < 0.001), mucinous subtype (P = 0.006), and age <60 years (P < 0.001) were identified as independent risk factors whereas deep submucosal invasion was only a dependent (P = 0.025) risk factor and not significant in multivariate analysis (P = 0.075). The incidence of LNM was 51/882 (6%) in absence of the independent risk factors. The Danish validation cohort, confirmed our findings regarding the role of submucosal invasion, LVI, and age. CONCLUSIONS: This is a large study on LNM in T1 CRC, including validation, showing that LVI and perineural invasion, mucinous subtype, and low age constitute independent risk factors, whereas depth of submucosal invasion is not an independent risk factor of LNM. Thus, our findings provide a useful basis for management of patients after local excision of early CRC.

Genomic evolution and diverse models of systemic metastases in colorectal cancer.

OBJECTIVE: The systemic spread of colorectal cancer (CRC) is dominated by the portal system and exhibits diverse patterns of metastasis without systematical genomic investigation. Here, we evaluated the genomic evolution of CRC with multiorgan metastases using multiregion sequencing. DESIGN: Whole-exome sequencing was performed on multiple regions (n=74) of matched primary tumour, adjacent non-cancerous mucosa, liver metastasis and lung metastasis from six patients with CRC. Phylogenetic reconstruction and evolutionary analyses were used to investigate the metastatic seeding pattern and clonal origin. Recurrent driver gene mutations were analysed across patients and validated in two independent cohorts. Metastatic assays were performed to examine the effect of the novel driver gene on the malignant behaviour of CRC cells. RESULTS: Based on the migration patterns and clonal origins, three models were revealed (sequential, branch-off and diaspora), which not only supported the anatomic assumption that CRC cells spread to lung after clonally expanding in the liver, but also illustrated the direct seeding of extrahepatic metastases from primary tumours independently. Unlike other cancer types, polyphyletic seeding occurs in CRC, which may result in late metastases with intermetastatic driver gene heterogeneity. In cases with rapid dissemination, we found recurrent trunk loss-of-function mutations in ZFP36L2, which is enriched in metastatic CRC and associated with poor overall survival. CRISPR/Cas9-mediated knockout of ZFP36L2 enhances the metastatic potential of CRC cells. CONCLUSION: Our results provide genomic evidence for metastatic evolution and indicate that biopsy/sequencing of metastases may be considered for patients with CRC with multiorgan or late postoperative metastasis.

Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Colorectal Peritoneal Metastases: A Systematic Review.

BACKGROUND: Combined treatment modality of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy is emerging as an alternative option for colorectal peritoneal metastases, but there is ambiguity regarding patient selection, treatment protocols, and efficacy. OBJECTIVE: To elaborate on the patient characteristics, hyperthermic intraperitoneal chemotherapy protocol and health outcomes in colorectal peritoneal metastases patients undergoing a combination of hyperthermic intraperitoneal chemotherapy and cytoreductive surgery and provide guidance for future studies. DATA SOURCES: A Medline search for English language studies published between 2004 and 2019. STUDY SELECTION: Medical subject headings and key terms, including: hyperthermic intraperitoneal chemotherapy, colorectal peritoneal metastases, colorectal cancer and combinations thereof as per guidelines. MAIN OUTCOME MEASURES: Overall survival, disease-free survival, and morbidity and mortality rates. RESULTS: Of the 26 included studies, 42% were published between 2016 and 2019. More than half of the studies were retrospective in nature and conducted in tertiary specialized centers outside of the United States. The median age range was 44 to 62 years. Mitomycin C-based therapy was seen in 50% of studies. Mean weighted median disease-free survival for 11 studies was 15 months (9 to 36 months). Median OS ranged from 12 to 63 months, with an average of 33.6 months among 20 studies. Overall morbidity varied from 11% to 56%, with a weighted mean of 29% in 18 studies. Mortality ranged from 0 to 34%, with a weighted mean of 4% in 15 studies. LIMITATIONS: Despite careful study selection, variability in methodology of the included studies can limit review findings. CONCLUSION: Due to study heterogeneity, and a recent large, randomized trial showing no overall benefit, use of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy in colorectal peritoneal metastases patients is highly controversial. Further standardized controlled studies can help uniformly define and build consensus among the medical community on patient eligibility and the optimal hyperthermic intraperitoneal chemotherapy techniques. PROSPERO: Registered on March 3, 2020, CRD42020146942.

Monitoramento do horizonte tecnológico: Medicamentos para tratamento de primeira linha do câncer colorretal metastático / Monitoring the technological horizon: Drugs for first-line treatment of metastatic colorectal cancer

A DOENÇA Os cânceres de cólon e reto, ou câncer colorretal, abrangem os tumores que acometem o intestino grosso (cólon) e o reto, sendo que cerca de 50% localizam-se no reto e sigmoide e 30% no ceco. Estima-se que, no mundo, no ano de 2020, o câncer colorretal (CCR) tenha sido, entre os tipos de neoplasias malignas, o terceiro mais diagnosticado e o segundo mais letal, com 1,9 milhões de casos novos e 935.000 óbitos. No Brasil, o CCR é considerado a segunda neoplasia maligna mais incidente entre homens e mulheres, desconsiderando os tumores de pele não melanoma. Para cada ano do triênio de 2020-2022, são estimados 20.520 casos em homens e 20.470 em mulheres. O risco estimado de novos casos é de 19,63 para cada 100 mil homens e 19,03 para cada 100 mil mulheres. Em 2019, foram registradas aproximadamente 20 mil mortes por câncer colorretal no Brasil. TRATAMENTOS SISTÊMICOS DE PRIMEIRA LINHA DISPONÍVEIS: Na Agência Nacional de Vigilância Sanitária (Anvisa) estão registrados dez medicamentos com indicação em bula para o CCRm, que podem compor diferentes esquemas terapêuticos. São eles: aflibercepte, bevacizumabe, capecitabina, cetuximabe, fluorouracil (5- FU), irinotecano, oxaliplatina, panitumumabe, pembrolizumabe, regorafenibe e trifluridina + tipiracila. As Diretrizes Diagnósticas e Terapêuticas (DDT) do Câncer de Cólon e Reto, publicada em 2014, estão em processo de atualização no momento22,23 . O CCRm irressecável não é alvo da versão atual em curso da diretriz supracitada, sendo seu tratamento apresentado de forma geral. Para os doentes com metástases hepáticas irressecáveis e ausência ou mínima invasão extra-hepática é recomendada a quimioterapia paliativa sistêmica baseada em fluoropirimidina contendo ou não oxaliplatina ou irinotecano, com o objetivo de reduzir o volume tumoral e permitir, assim, a ressecção cirúrgica. De acordo com a DDT, existe evidência de que o uso de esquema terapêutico associado ao cetuximabe ou bevacizumabe promove uma taxa de ressecabilidade maior que controles históricos, entretanto, na época da sua elaboração (busca realizada em 2012) ainda existia incerteza quanto ao significado clínico em termos de benefícios clínicos duradouros ou ganho de sobrevida. ESTRATÉGIA DE BUSCA: Os medicamentos em fase de desenvolvimento para o tratamento de primeira linha de pacientes com CCRm foram identificados, inicialmente, na base de pesquisa clínica Clinicatrials.gov em 01 de julho de 2021 e atualizado em 15 de outubro de 2021, com filtro para estudo de intervenção, na fase 3 de ensaio clínico e em andamento (situação do recrutamento: ativo, não recrutando ainda, ativo sem recrutamento, inscrição por convite). TECNOLOGIAS EM DESENVOLVIMENTO: A busca inicial no Clinicaltrials.gov retornou 52 registros de ensaios clínicos, dentre os quais onze ensaios foram selecionados a partir dos critérios de elegibilidade definidos. A partir desses ensaios clínicos foram identificados oito medicamentos potenciais em desenvolvimento nas classes: inibidores checkpoint imunológico PD-1, inibidor do receptor do fator de crescimento epidérmico, inibidor multi-tirosina quinase e inibidor da proteína quinase BRAF. CONSIDERAÇÕES FINAIS: Em 2020, o câncer colorretal (CCR) foi o terceiro tipo de câncer mais incidente e a segunda causa mais comum de mortes relacionadas ao câncer no mundo2 . Quando detectado precocemente e sem a presença de metástase em outros órgãos o CCR pode ser tratado e curado. Entretanto, quando há a presença de metástases não ressecáveis, o quadro clínico é de pior prognóstico. Nas últimas duas décadas, o tratamento de câncer colorretal metastático (CCRm) teve avanços com a aprovação de novos medicamentos citotóxicos e de terapia-alvo. As classes de inibidores do receptor do fator de crescimento endotelial vascular (cetuximabe e panitumumabe) e do receptor do fator de crescimento epidérmico (bevacizumabe) representaram um aumento na sobrevida dos pacientes com CCR. Apesar dos ganhos em sobrevida global e sobrevida livre de progressão da doença com as diferentes combinações de esquemas terapêuticos entre quimioterápicos e biológicos, o componente genético característico do CCR tem importante influência sobre o desempenho dos tratamentos entre os pacientes. Este informe de Monitoramento do Horizonte Tecnológico identificou oito tecnologias que se encontram em fase 3 de ensaio clínico para o tratamento de primeira linha do CCRm, inclusive pela via oral para maior comodidade posológica dos pacientes. Entre as classes dos medicamentos estão os inibidores de pontos de verificação imunológico PD-1 (checkpoint), inibidores do receptor do fator de crescimento epidérmico, inibidores multi-tirosina quinase e inibidores da proteína quinase BRAF. Na classe de inibidores checkpoint imunológico PD-1 foram identificadas cinco tecnologias (atezolizumabe, nivolumabe, serplulimabe, sintilimabe e imunoterapia com células autólogas). O atezolizumabe, nivolumabe, serplulimabe e o sintilimabe são anticorpos monoclonais humanizados direcionados ao receptor de morte programada. O nivolumabe é registrado no FDA e EMA para pacientes com CCRm com a presença confirmada de instabilidade de microssatélites elevada (MSI-H ­ microsatellite instability-high) ou deficiência de reparação por incompatibilidade (dMMR ­ mismatch repair deficient). O atezolizumabe também está sendo estudado para os pacientes com CCRm e presença de MSI-H e dMMR. O serplulimabe e sintilimabe iniciaram seus ensaios clínicos de fase 3 recentemente, em 2020 e 2021, respectivamente e não apresentam resultados parciais publicados. Os resultados da fase anterior (fase 2) em outras linhas de tratamento demostraram que o serplulimabe apresentou uma taxa de resposta objetiva em torno de 38% para os tumores com MSI-H e dMMR, incluindo o CCR. A imunoterapia de células autólogas é uma terapia avançada na qual os linfócitos T autólogos são retirados e ativados para ter como alvo o receptor de morte programada-1 e assim retornam ao mesmo paciente para desempenhar melhor seu papel imunológico de modo direcionado ao tumor. Os resultados de fase 3 também não foram publicados até o momento da busca. Após a expiração da patente do medicamento cetuximabe de referência, algumas empresas começaram a desenvolver biossimilares. Atualmente, existem alguns ensaios clínicos em andamento em diversas fases com o cetuximabe biossimilar para a indicação de CCR metastático. Não foram identificados resultados publicados para a fase 3 em andamento para o tratamento de primeira linha, entretanto resultados para a segunda linha de tratamento de CCR metastático indicaram que o CMAB009 (um dos códigos de biossimilares sendo estudado) aumentou a taxa de resposta global em relação ao irinotecano em monoterapia. Outro medicamento, o anlotinibe foi identificado na classe de inibidores multitirosina quinase, que possui ação em vários receptores que implicam no crescimento tumoral, na angiogênese e na progressão metastática do câncer. Os ensaios clínicos de fase 3 ainda estão em andamento com previsão de finalização em 2024. Resultados preliminares de fase 2 com o anlotinibe indicaram melhora em alguns desfechos. Por fim, foi identificado o medicamento encorafenibe, pertencente à classe de inibidor da proteína quinase BRAF, que possui resultados promissores em estudos de fase 2, tendo sido registrado, recentemente, nas agências EMA e FDA para os pacientes com CCR metastático com gene BRAF V600E mutado que apresentaram progressão com tratamentos anteriores. Motivados por esses resultados promissores em linhas posteriores de tratamento o esquema terapêutico com o encorafenibe associado a outros medicamentos vem sendo testado na população de pacientes com CCRm BRAF V600 mutado sem tratamento prévio. Os ensaios clínicos de todos os medicamentos identificados específicos para tratamento de primeira linha estão em andamento com previsão de finalização até 2025. De modo que é preciso continuar seu monitoramento a fim de observar os resultados e os impactos que as tecnologias estudadas possam apresentar no tratamento inicial dos pacientes com CCR metastático.

Deep learning for the prediction of early on-treatment response in metastatic colorectal cancer from serial medical imaging.

In current clinical practice, tumor response assessment is usually based on tumor size change on serial computerized tomography (CT) scan images. However, evaluation of tumor response to anti-vascular endothelial growth factor therapies in metastatic colorectal cancer (mCRC) is limited because morphological change in tumor may occur earlier than tumor size change. Here we present an analysis utilizing a deep learning (DL) network to characterize tumor morphological change for response assessment in mCRC patients. We retrospectively analyzed 1,028 mCRC patients who were prospectively included in the VELOUR trial (NCT00561470). We found that DL network was able to predict early on-treatment response in mCRC and showed better performance than its size-based counterpart with C-Index: 0.649 (95% CI: 0.619,0.679) vs. 0.627 (95% CI: 0.567,0.638), p = 0.009, z-test. The integration of DL network with size-based methodology could further improve the prediction performance to C-Index: 0.694 (95% CI: 0.661,0.720), which was superior to size/DL-based-only models (all p < 0.001, z-test). Our study suggests that DL network could provide a noninvasive mean for quantitative and comprehensive characterization of tumor morphological change, which may potentially benefit personalized early on-treatment decision making.

Lymphocyte-to-C-Reactive Protein Ratio Is the Most Sensitive Inflammation-Based Prognostic Score in Patients With Unresectable Metastatic Colorectal Cancer.

BACKGROUND: Systemic inflammation contributes to the progression of malignancies. The preoperative lymphocyte-to-C-reactive protein ratio has recently been shown to predict survival of patients with colorectal cancer who undergo surgery, but its prognostic value remains unclear in patients with unresectable metastatic colorectal cancer. OBJECTIVE: This study aimed to examine the prognostic values of inflammation-based prognostic scores in patients with metastatic colorectal cancer, focusing on the lymphocyte-to-C-reactive protein ratio. DESIGN: This is a retrospective study from a prospectively collected database. SETTINGS: This study was conducted at a high-volume multidisciplinary tertiary cancer center in Japan. PATIENTS: The subjects were 756 consecutive patients with unresectable metastatic colorectal cancer who received systemic chemotherapy from 2000 to 2015. The prognostic value of the lymphocyte-to-C-reactive protein ratio was evaluated by univariable and multivariable analyses. Time-dependent receiver operating characteristics curve analysis was conducted to compare the prognostic impact of the lymphocyte-to-C-reactive protein ratio with the impact of the neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, or the modified Glasgow Prognostic Score. MAIN OUTCOME MEASURES: The primary outcomes measured were the correlations of prognostic scores with overall survival. RESULTS: Median survival times of patients with high, intermediate, and low lymphocyte-to-C-reactive protein ratios were 29.4, 19.3, and 13.1 months (p < 0.001). In all subgroups according to key prognostic factors (performance status, use of targeted agents, pretreatment CEA levels, tumor sidedness, M category, and primary tumor resection), patient prognosis could be clearly stratified into 3 groups by the lymphocyte-to-C-reactive protein ratio. Multivariable analysis revealed that decreased lymphocyte-to-C-reactive protein ratio was independently associated with reduced survival (low vs high: HR 1.96, p < 0.001; intermediate vs high: HR 1.44, p < 0.001). The time-dependent receiver operating characteristics curve analysis revealed that the lymphocyte-to-C-reactive protein ratio was the most sensitive predictor of survival among all inflammation-based prognostic scores on a continuous basis. LIMITATIONS: This study was retrospective in nature. CONCLUSIONS: The lymphocyte-to-C-reactive protein ratio is a useful prognostic biomarker for unresectable metastatic colorectal cancer and could contribute to accurate prognostication and therapeutic decision making. See Video Abstract at http://links.lww.com/DCR/B600. RELACIN ENTRE LINFOCITOS Y PROTENA C ES EL SCORE PRONOSTICO INFLAMATORIO MAS SENSIBLE EN PACIENTES CON CNCER COLORRECTAL METASTSICO IRRESECABLE: ANTECEDENTES:La inflamación sistémica contribuye en la progresión de neoplasias malignas. Recientemente se ha demostrado que la proporción preoperatoria de linfocitos -proteína C reactiva predice la supervivencia de los pacientes con cáncer colorrectal que se sometieron a cirugía, pero su valor pronóstico sigue sin estar claro en pacientes con cáncer colorrectal metastásico irresecable.OBJETIVO:Evaluar el valor pronostico de los scores inflamtorios centrandose en linfocito- proteina c reactiva en pacientes con cáncer colorrectal metastásico.DISEÑO:Estudio retrospective evaluando una base de datos.AJUSTE:Este estudio se llevó a cabo en un centro oncológico terciario multidisciplinario de gran volumen en Japón.PACIENTES:Se incluyeron 756 pacientes consecutivos todos con cáncer colorrectal metastásico irresecable que recibieron quimioterapia sistémica de 2000 a 2015. El valor pronóstico de la proteína C reactiva se evaluó mediante análisis univariables y multivariables. Se realizó análisis de la curva de características operativas del receptor dependiente del tiempo para comparar el impacto pronóstico de la proteína linfocito-C-reactiva con el de la proporción de neutrófilos a linfocitos, la proporción de plaquetas a linfocitos, la proporción de linfocitos a monocitos o la proporción de puntuación pronóstica segun escala de Glasgow modificada.PRINCIPALES MEDIDAS DE RESULTADO:Correlacion de las puntuaciones pronósticas con la supervivencia global.RESULTADOS:La mediana de supervivencia de los pacientes con niveles altos, intermedios y bajos de proteína C reactiva de linfocitos fue de 29,4, 19,3 y 13,1 meses, respectivamente (p <0,001). En todos los subgrupos de acuerdo con los factores pronósticos clave (estado funcional, uso de agentes dirigidos, niveles de antígeno carcinoembrionario antes del tratamiento, lado del tumor, categoría M y resección del tumor primario), el pronóstico del paciente podría estratificarse claramente en tres grupos por linfocito a C- proteína reactiva. El análisis multivariable reveló que la disminución de linfocitos a proteína C reactiva se asoció de forma independiente con una supervivencia reducida (baja frente a alta: cociente de riesgo 1,96, p <0,001; intermedio frente a alto: cociente de riesgo 1,44, p <0,001). El análisis de la curva de características operativas del receptor dependiente del tiempo reveló que de linfocito a proteína C reactiva era el predictor de supervivencia más sensible entre todas las puntuaciones de pronóstico basadas en inflamación de forma continua.LIMITACIONES:Este estudio fue de naturaleza retrospectiva.CONCLUSIONES:La proteína C reactiva de linfocitos a C es un biomarcador pronóstico útil para el cáncer colorrectal metastásico irresecable y podría contribuir a un pronóstico preciso y a la toma de decisiones terapéuticas. Consulte Video Resumen en http://links.lww.com/DCR/B600.

Real-world use of bevacizumab-awwb, a bevacizumab biosimilar, in US patients with metastatic colorectal cancer.

Aim: Evaluated real world use of bevacizumab-awwb (MVASI®), a bevacizumab biosimilar, for treating metastatic colorectal cancer (mCRC). Materials & methods: Adult mCRC patients who received bevacizumab-awwb during the first year after market availability were identified from the ConcertAI oncology dataset. Results: Of 304 patients, 47% initiated bevacizumab-awwb as reference product (RP) naive patients and 53% received bevacizumab-awwb with prior exposure to RP. Overall, 78% received bevacizumab-awwb as first-line therapy; the proportion was higher (91%) in RP-naive patients. Among RP-experienced patients, 83% were transitioned from RP to bevacizumab-awwb in the same line without disease progression; of those, the majority (83%) were transitioned within 28 days. Conclusion: Early evidence from US oncology practices suggests clinical adoption of bevacizumab-awwb in treating mCRC patients.

E-Cadherin and Angiopoietin-2 as Potential Biomarkers for Colorectal Cancer With Peritoneal Carcinomatosis.

BACKGROUND/AIM: E-Cadherin has been implicated in cell-cell adhesion, and soluble E-cadherin is involved in angiogenesis and resistance to anti-angiogenic therapy in several cancer types. This study aimed to investigate the expression and clinical significance of soluble E-cadherin and other angiogenesis-related factors in plasma and malignant ascites of colorectal cancer (CRC) in patients with peritoneal carcinomatosis (PC). MATERIALS AND METHODS: Multiplex enzyme-linked immunosorbent assay was performed on 95 body fluid samples (57 plasma and 38 malignant ascites) from patients with CRC. The status of E-cadherin and angiopoietin-2 (AGNPT2) was retrospectively evaluated by immunohistochemistry in primary CRC and paired metastatic peritoneal tissues or cell blocks of malignant ascites of 30 patients with peritoneal metastases of CRC. RESULTS: The expression levels of soluble E-cadherin and ANGPT2 in plasma samples were significantly increased in patients with PC compared with those without. E-Cadherin concentration was significantly lower and ANGPT2 concentration was significantly higher in malignant ascites than plasma samples. Expression of E-cadherin was strongly positive, whilst that of ANGPT2 was negative in primary colorectal tissues, metastatic peritoneal tissues, and cell blocks of malignant ascites by immunohistochemistry. High levels of soluble E-cadherin or ANGPT2 in ascites were negatively associated with overall survival in patients with CRC with malignant ascites. CONCLUSION: Our findings suggest that soluble E-cadherin and ANGPT2 may be surrogate biomarkers for clinical outcome in patients with PC from CRC.

Racial differences in survival and response to therapy in patients with metastatic colorectal cancer: A secondary analysis of CALGB/SWOG 80405 (Alliance A151931).

BACKGROUND: The objective of this study was to evaluate the association between self-identified race and overall survival (OS), progression-free survival (PFS), and response to therapy among patients enrolled in the randomized Cancer and Leukemia Group B (CALGB)/SWOG 80405 trial. METHODS: Patients with advanced or metastatic colorectal cancer who were enrolled in the CALGB/SWOG 80405 trial were identified by race. On the basis of covariates (treatment arm, KRAS status, sex, age, and body mass index), each Black patient was exact matched with a White patient. The association between race and OS and PFS was examined using a marginal Cox proportional hazard model for matched pairs. The interaction between KRAS status and race was tested in the model. The association between race and response to therapy and adverse events were examined using a marginal logistic regression model. RESULTS: In total, 392 patients were matched and included in the final data set. No difference in OS (hazard ratio [HR], 0.92; 95% confidence interval [CI], 0.73-1.16), PFS (HR, 0.97; 95% CI, 0.78-1.20), or response to therapy (odds ratio [OR], 1.00; 95% CI, 0.65-1.52) was observed between Black and White patients. Patients with KRAS mutant status (HR, 1.31; 95% CI, 1.02-1.67), a performance statusscore of 1 (reference, a performance status of 0; HR, 1.49; 95% CI, 1.18-1.88), or ≥3 metastatic sites (reference, 1 metastatic site; HR, 1.67; 95% CI, 1.22-2.28) experienced worse OS. Black patients experienced lower rates and risk of grade ≥3 fatigue (6.6% vs 13.3%; OR, 0.46; 95% CI, 0.24-0.91) but were equally likely to be treated with a dose reduction (OR, 1.09; 95% CI, 0.72-1.65). CONCLUSIONS: No difference in OS, PFS, or response to therapy was observed between Black patients and White patients in an equal treatment setting of the CALGB/SWOG 80405 randomized controlled trial. LAY SUMMARY: Despite improvements in screening and treatment, studies have demonstrated worse outcomes in Black patients with colorectal cancer. The purpose of this study was to determine whether there was a difference in cancer-specific outcomes among Black and White patients receiving equivalent treatment on the CALGB/SWOG 80405 randomized clinical trial. In this study, there was no difference in overall survival, progression-free survival, or response to therapy between Black and White patients treated on a clinical trial. These findings suggest that access to care and differences in treatment may be responsible for racial disparities in colorectal cancer.

Histopathological risk factors for lymph node metastases in T1 colorectal cancer: meta-analysis.

BACKGROUND: National screening programmes increase the proportion of T1 colorectal cancers. Local excision may be possible, but the risk of lymph node metastases (LNMs) could jeopardize long-term outcomes. The aim of the present study was to review the association between histopathological findings and LNMs in T1 colorectal cancer. METHODS: A systematic literature search was conducted using PubMed,Embase, and Cochrane online databases. Studies investigating the association between one or more histopathological factors and LNMs in patients who underwent resection for T1 colorectal cancer were included. RESULTS: Sixteen observational studies were included in the meta-analysis, including a total of 10 181 patients, of whom 1 307 had LNMs. Lymphovascular invasion (odds ratio (OR) 7.42; P < 0.001), tumour budding (OR 4.00; P < 0.001), depth of submucosal invasion, whether measured as at least 1000 µm (OR 3.53; P < 0.001) or Sm2-3 (OR 2.12; P = 0.020), high tumour grade (OR 3.75; P < 0.001), polypoid growth pattern (OR 1.59; P = 0.040), and rectal location of tumour (OR 1.36; P = 0.003) were associated with LNMs. CONCLUSION: Distinct histopathological factors associated with nodal metastases in T1 colorectal cancer can aid selection of patients for local excision or major excisional surgery.

mSEPT9 Can Monitor the Response and Predict the Prognosis of Stage IV Colorectal Cancer Patients with Liver Metastasis Undergoing Potentially Curative Surgery.

BACKGROUND: Stage IV colorectal cancer (CRC) patients with liver metastasis undergoing potentially curative surgery represent a subgroup of patients with a relatively good prognosis. In this study, we aimed to evaluate the performance of mSEPT9 to monitor response to treatment and predict prognosis. METHODS: In total, we recruited 51 stage IV CRC patients with liver metastasis, including 20 patients who underwent simultaneous surgery and 31 patients who underwent staged surgery. We measured the blood levels of mSEPT9 and CEA prior to surgery and then seven days after surgery. RESULTS: mSEPT9 and CEA were detected prior to surgery in 92.2% (47/51) and 70.6% (36/51) of patients, respectively. Following simultaneous and staged surgery, levels of mSEPT9 fell significantly by 923-fold (P<0.001) and 11-fold (P<0.001), respectively. Levels of CEA also fell significantly by 17-fold (P<0.001) and 1.7-fold (P<0.01) following simultaneous and staged surgery, respectively. The mean percentage reduction of mSEPT9 levels after simultaneous surgery (12.3%) was significantly lower than that of staged surgery (33.8%) (P<0.001) while the mean percentage reduction of CEA levels after simultaneous surgery (35.5%) were significantly lower than that of staged surgery (64.6%) (P<0.05). The levels of mSEPT9 in the blood were quantitatively correlated with tumor burden. Survival analysis showed that patients who tested negative for mSEPT9 pre- and post-surgery had a better survival rate than those who tested positive, thus suggesting that mSEPT9 can act as a prognostic indicator. CONCLUSIONS: mSEPT9 showed good quantitative efficacy, higher applicability, and sensitivity, than CEA in assessing treatment response and prognosis prediction in patients with stage IV CRC and liver metastasis.

Mutational profiles of metastatic colorectal cancer treated with FOLFIRI plus cetuximab or bevacizumab before and after secondary resection (AIO KRK 0306; FIRE-3).

Secondary resection of metastases is recommended in metastatic colorectal cancer (mCRC). Data describing changes in mutational profiles of corresponding primary tumor and metastatic tissue after conversion treatment are limited. Next generation sequencing was performed in formalin-fixed mCRC samples from patients of the FIRE-3 trial (FOLFIRI plus cetuximab or bevacizumab) before treatment start (baseline) and after secondary resection of metastases (post baseline). Changes of mutational profiles and tumor mutational burden (TMB) were assessed within a post-hoc analysis. Median overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) were compared between treatment arms. Paired tumor samples were obtained from 25 patients (19 RAS wild-type, 6 RAS mutant by pyrosequencing). ORR (92.0% vs 58.0%) and OS (60.8 vs 35.4 months, hazard ratio = 0.39 [95% CI 0.14-1.12], P = .08) were higher for patients receiving cetuximab. After conversion therapy, 56 alterations (42 in the cetuximab and 14 in the bevacizumab arm) were newly observed in 18 patients (9 each treated with cetuximab or bevacizumab). Gains (n = 21) and losses (n = 21) of alterations occurred during cetuximab-based treatment, while mainly gains of alterations occurred during bevacizumab (n = 10). Three of nine patients treated with cetuximab that presented a change of mutational profiles, developed resistance to cetuximab. Mutational profiles were largely comparable before and after treatment with anti-VEGF or anti-EGFR directed monoclonal antibodies after secondary resection. Mutations associated with resistance to anti-EGFR antibodies were observed in only one-third of patients.

Assessment of exposure-response relationship for bevacizumab in patients with metastatic colorectal cancer.

Limited literature is available for bevacizumab exposure-response relationship and there is not a concentration threshold associated with an optimal disease control. This prospective observational study in patients with metastatic colorectal cancer (mCRC) aims to evaluate, in a real-life setting, the relationship between bevacizumab through concentrations at steady state (Ctrough, SS) and disease control. Ctrough, SS were drawn, coinciding with the radiological evaluation of the response (progression or clinical benefit). Generalized estimating equations (GEE) analysis was performed. To test the association between Ctrough, SS in each patient with overall survival (OS) or progression-free survival (PFS), Cox proportional hazard models were developed. Data included 50 bevacizumab Ctrough, SS from 27 patients. The GEE model did not suggest any positive association between bevacizumab Ctrough, SS and clinical benefit (OR 0.99, 95% CI: 0.98-1.02, p = 0.863). The Cox regression showed association between higher median Ctrough, SS with better OS (HR 0.86, 95% CI: 0.73-1.01, p = 0.060), but not with PFS. We cannot confirm a relationship between bevacizumab Ctrough, SS and clinical benefit but this is the first real-world study trying to show a relationship between bevacizumab Ctrough, SS and disease control in mCRC. It was conducted in a small sample size which reduces the level of evidence. Further controlled randomized studies with a sufficient number of patients are required.

Claudin-2 promotes colorectal cancer liver metastasis and is a biomarker of the replacement type growth pattern.

Claudin-2 promotes breast cancer liver metastasis by enabling seeding and early cancer cell survival. We now demonstrate that Claudin-2 is functionally required for colorectal cancer liver metastasis and that Claudin-2 expression in primary colorectal cancers is associated with poor overall and liver metastasis-free survival. We have examined the role of Claudin-2, and other claudin family members, as potential prognostic biomarkers of the desmoplastic and replacement histopathological growth pattern associated with colorectal cancer liver metastases. Immunohistochemical analysis revealed higher Claudin-2 levels in replacement type metastases when compared to those with desmoplastic features. In contrast, Claudin-8 was highly expressed in desmoplastic colorectal cancer liver metastases. Similar observations were made following immunohistochemical staining of patient-derived xenografts (PDXs) that we have established, which faithfully retain the histopathology of desmoplastic or replacement type colorectal cancer liver metastases. We provide evidence that Claudin-2 status in patient-derived extracellular vesicles may serve as a relevant prognostic biomarker to predict whether colorectal cancer patients have developed replacement type liver metastases. Such a biomarker will be a valuable tool in designing optimal treatment strategies to better manage patients with colorectal cancer liver metastases.