Correction to: Accelerating Therapeutic Development through Innovative Trial Design in Colorectal Cancer.

In the original version of this article, which published in Volume 19, Issue 2 (February 2018), the third author's name was captured incorrectly. The proper name is now provided.

The impact of complete chemotherapy stop on the overall survival of patients with advanced colorectal cancer in first-line setting: A meta-analysis of randomized trials.

BACKGROUND: The impact of the duration of chemotherapy on the overall survival of patients with metastatic colorectal cancer (mCRC) is controversial and studies have failed to define a clear standard. METHODS: We searched medical literature databases and oncology conferences proceedings for randomized controlled trials (RCT) that compared the overall survival of mCRC patients who received continuous first-line chemotherapy until disease progression versus those who were offered complete treatment stop after a fixed number of cycles. Studies including targeted agents were also included. A meta-analysis of reported hazard ratios (HRs) for survival was performed. RESULTS: We retrieved 240 trials, of which six were eligible and five were included in the pooled analysis of overall survival (N = 3061). The overall survival between continuously delivered chemotherapy and complete stop was not statistically different (HR = 0.93, 95% CI 0.85-1.02; p = 0.12; I² = 5%). The results are similar when we analyzed separately the trials performing randomization before versus after induction therapy. The median chemotherapy free interval in the complete stop group was 3.9 months (3.6-4.3 months). Chemotherapy administered until progression was associated with more adverse effects and impaired quality of life. CONCLUSION: Compared with first-line continuous chemotherapy administered until disease progression, complete treatment stop did not have a detrimental impact on the overall survival of patients with mCRC. Identification of predictive biomarkers could help clinicians to select the patients who would benefit from continuous cancer-directed therapies.

Survival and Response Outcomes for Gastrointestinal Neuroendocrine Tumor (GEP-NETs) Patients Treated with Lutetium-177-DOTATATE in a Brazilian Reference Center: A Six-Year Follow-Up Experience.

BACKGROUND: PRRT can be an option for all-grade GEP-NETs, but selecting patients is challenging. In this scenario, clinical-pathological and radiological characteristics, such as pre-treatment Ga-68 DOTA PET/CT, might have the potential to help. METHODS: A retrospective chart review was conducted on advanced GEP-NETs treated with at least one PRRT dose. Overall survival (OS) and progression-free survival (PFS) were calculated using the Kaplan-Meier method. Krenning Score (KS), and the maximum standardized uptake value (SUVmax) were derived from the pre-treatment scans. A maximally selected rank statistics test was used for SUVmax simple cut point estimate. RESULTS: Among 36 patients, 19 had primary pancreatic tumors. The numbers of G1, G2, and G3 tumors were 10, 18, and 7, respectively. During a median follow-up of 90.5 months, 4 patients died. Median OS was not reached for G1 and G2 tumors, and it was 30 months for G3 (p = 0.001). Median PFS was 23 months, with G3 showing lower PFS compared to G1 [7 versus 30 months; HR 8.41 (95%CI 2.2-31.0; p = 0.001)]. CONCLUSIONS: PRRT provides long-term PFS in patients with G1/G2 GEP-NETs independent of clinical characteristics and primary site. G3 has worse survival, but selected patients may experience long OS after PRRT treatment.

Real-World Evidence on the Use of Endocrine Therapy for Ductal Carcinoma In Situ in Patients Treated With Breast-Conserving Surgery Followed by Postoperative Radiation Therapy: A Brazilian Retrospective Cohort Study.

INTRODUCTION/BACKGROUND: This study aims to evaluate the reproducibility of findings from randomized controlled trials regarding adjuvant hormone therapy (HT) for breast ductal carcinoma in situ (DCIS) in a real-life scenario. MATERIALS/METHODS: This retrospective cohort study used Fundação Oncocentro de São Paulo database. It included DCIS patients DCIS who received breast-conserving surgery and postoperative radiation therapy. The endpoints were local control (LC), breast cancer-specific survival (BCSS), and overall survival (OS). RESULTS: We analyzed 2192 patients treated between 2000 and 2020. The median FU was 48.99 months. Most patients (53.33%; n = 1169) received adjuvant HT. Patients not receiving adjuvant HT tend to be older (P = .021) and have a lower educational level (P < .001). At the end of FU, 1.5% of patients had local recurrence, and there was no significant difference between groups (P = .19). The 10-year OS and BCSS were 89.4% and 97.5% for adjuvant HT versus 91.5% and 98.5% for no adjuvant HT, respectively, and there were no significant differences between groups. The 10-year OS was 93.25% for medium/high education level versus 87.31% for low (HR for death 0.51; 95% CI, 0.32-0.83; P = .007). CONCLUSIONS: The benefits of adjuvant HT for DCIS were not reproduced in a Brazilian cohort. Education significantly impacted survival and HT usage, reflecting the influence of socioeconomic factors. These findings can allow for more precise interventions.

Breast Cancer Phenotype Associated With Li-Fraumeni Syndrome: A Brazilian Cohort Enriched by TP53 p.R337H Carriers.

Breast cancer (BC) is the most prevalent malignancy in women with Li-Fraumeni syndrome (LFS). The literature on BC in LFS is limited due to its rarity worldwide. A TP53 founder pathogenic variant (c.1010G>A; p.R337H) is responsible for the higher prevalence of this syndrome among women of Brazilian ancestry. Purpose: The aim of the study was to describe the BC phenotype expressed by Brazilian female LFS carriers and compare the data between p.R337H and other TP53 germline pathogenic/likely pathogenic variants (non-p.R337H carriers). Methods: We searched for cases of TP53 germline pathogenic/likely pathogenic variant carriers affected by BC included between 2015 and 2020 in the BLiSS (Brazilian Li-Fraumeni Study) registry at the Sírio-Libanês Hospital. Results: Among 163 adult female carriers from the registry, 91 (56%) had received a BC diagnosis, including 72 p.R337H carriers. BC was the first cancer diagnosed in 90% of cases. Early onset BC (age ≤45 years) was diagnosed in 78.2% of cases (11.5% <31 years; 66.7% 31-45 years; 21.8% >45 years). The median age of BC diagnosis for p.R337H carriers was 39.5 years (range 20-69 years) compared to 34 years (range 21-63 years) for non-p.R337H carriers (p = 0.009). In total, 104 breast tumors were observed in 87 women. Bilateral BC was observed in 29.3% of cases. Histology was available for 96 tumors, comprising 69 invasive breast carcinomas, which were mostly invasive ductal carcinomas (95.6%), 25 ductal in situ carcinomas and 2 soft-tissue sarcomas. Overall, 90.5% of invasive breast carcinomas were hormone receptor (HR)-positive, 39.5% were human epidermal growth factor receptor 2 (HER2)-positive, and 32.8% showed HR and HER2 co-expression. In addition, 55.4% of patients opted for contralateral prophylactic mastectomy after a first BC diagnosis. There were no significant differences in the risk of developing contralateral BC or in the immunohistochemical profile between p.R337H and non-p.R337H groups. Conclusions: The expressed phenotype of p.R337H is similar to that of other TP53 pathogenic/likely pathogenic variants, except for an average older age at the onset of disease; however, this is still younger than the general population.

A Prospective Cohort Study of Biomarkers in Squamous Cell Carcinoma of the Anal Canal (SCCAC) and their Influence on Treatment Outcomes.

Background: Although Chemoradiation (CRT) is the curative treatment for SCCAC, many patients present primary resistance. Since it is a rare tumor, response predictors remain unknown. Methods: We performed a prospective cohort study to evaluate biomarkers associated with CRT response, progression-free survival (PFS), and overall survival (OS). The primary endpoint was response at 6 months (m). Tumor DNA and HPV were analyzed by next-generation sequencing, while KI-67 and PD-L1 by immunohistochemistry in tumor tissue. Results: Seventy-eight patients were recruited between October/2011 and December/2015, and 75 were response evaluable. The median age was 57 years, 65% (n=49) were stage III and 12% (n=9) were HIV positive (HIV+). At 6m, 62.7% (n=47) presented CR. On multivariate analyses, stage II patients were 4.7 more likely to achieve response than stage III (OR, 4.70; 95%CI, 1.36-16.30; p=0.015). HIV+ was associated with a worse response (OR, 5.72; 95%CI, 2.5-13.0; p<0.001). 5-year PFS and OS rates were 63.3% and 76.4%, respectively, with a median follow up of 66m. On multivariate analyses, older age (HR 1.06, p=0.022, 95%IC 1.01-1.11) and absence of CR at 6m (HR 3.36, p=0.007, 95%IC 1.39-8.09) were associated with inferior OS. The 5-year OS rate was 62.5% in HIV+ group compared to 78% among HIV- pts, although this difference was not statistically significant (p=0.4). PIK3CA, MET and TP53 mutations, HPV, Ki-67 expression, and PD-L1 expression, were not associated with PFS and OS. Conclusions: Clinical stage III and HIV+ were associated with worse response to CRT at 6m. The absence of CR was the main factor associated with poor 5-year OS.

Social determinants of health and survival on Brazilian patients with glioblastoma: a retrospective analysis of a large populational database.

Background: The majority of patients diagnosed with glioblastoma develop recurrent disease resulting in poor prognoses. The current study aimed to determine the survival rates of patients diagnosed with glioblastoma in Brazil accounting for the influence of age, treatment modalities, public and private practices, and educational level using a population-based national database. Methods: Patients diagnosed with glioblastoma from 1999-2020 were identified from The Fundação Oncocentro de São Paulo database to create a retrospective cohort. Patients were described according to age, education level treatment modalities and medical practice. In a Cox proportional hazards model, controlled for confounding factors for overall survival, the hazard ratio and 95% CI of overall survival in adults was evaluated. Findings: A total of 4,511 patients were included. The median lengths of survival for patients treated in the public and private settings were 8 and 17 months (p<0.001), respectively. Young patients had longer median overall survival (OS: 18 to 40 years, 41 to 60 years, 61 to 65 years, 66 to 70 years and over than 70 years was 22 months, 10 months, 6 months, 5 months, 4 months, respectively (p<0.001). In general, combined treatments were associated with higher median survival compared to monotherapy. The higher educational level, the higher median survival was observed (4 months for illiterate versus 14 months for university degree). In the multivariable analyses, the significant independent predictors for overall survival were practice setting, educational level, age and treatment modalities. Interpretation: Public practice, older patients, less intensive treatment, and lower educational level were associated with worse survival outcomes in Brazilian glioblastoma patients.

Identification of Actionable Fusions as an Anti-EGFR Resistance Mechanism Using a Circulating Tumor DNA Assay.

PURPOSE: Gene fusions are established oncogenic drivers and emerging therapeutic targets in advanced colorectal cancer. This study aimed to detail the frequencies and clinicopathological features of gene fusions in colorectal cancer using a circulating tumor DNA assay. METHODS: Circulating tumor DNA samples in patients with advanced colorectal cancer were analyzed at 4,581 unique time points using a validated plasma-based multigene assay that includes assessment of fusions in FGFR2, FGFR3, RET, ALK, NTRK1, and ROS1. Associations between fusions and clinicopathological features were measured using Fisher's exact test. Relative frequencies of genomic alterations were compared between fusion-present and fusion-absent cases using an unpaired t test. RESULTS: Forty-four unique fusions were identified in 40 (1.1%) of the 3,808 patients with circulating tumor DNA detected: RET (n = 6; 36% of all fusions detected), FGFR3 (n = 2; 27%), ALK (n = 10, 23%), NTRK1 (n = 3; 7%), ROS1 (n = 2; 5%), and FGFR2 (n = 1; 2%). Relative to nonfusion variants detected, fusions were more likely to be subclonal (odds ratio, 8.2; 95% CI, 2.94 to 23.00; P < .001). Mutations associated with a previously reported anti-epidermal growth factor receptor (anti-EGFR) therapy resistance signature (subclonal RAS and EGFR mutations) were found with fusions in FGFR3 (10 of 12 patients), RET (nine of 16 patients), and ALK (seven of 10 patients). For the 27 patients with available clinical histories, 21 (78%) had EGFR monoclonal antibody treatment before fusion detection. CONCLUSION: Diverse and potentially actionable fusions can be detected using a circulating tumor DNA assay in patients with advanced colorectal cancer. Distribution of coexisting subclonal mutations in EGFR, KRAS, and NRAS in a subset of the patients with fusion-present colorectal cancer suggests that these fusions may arise as a novel mechanism of resistance to anti-EGFR therapies in patients with metastatic colorectal cancer.

Value of Systemic Staging in Asymptomatic Early Breast Cancer.

OBJECTIVE: Metastases are rare in early breast cancer (EBC), and international guidelines recommend against routine systemic staging for asymptomatic patients. However, imaging exams remain widely employed in the clinical practice. The aim of the present study is to evaluate the value of imaging for systemic staging in EBC. METHODS: A retrospective analysis of newly-diagnosed breast cancer (BC) patients was performed. Clinical data including BC subtype, stage, presence of symptoms at diagnosis and instrumental procedures performed for staging were recorded. RESULTS: A total of 753 patients were included, with a median age of 57 years. The majority of the patients underwent at least 1 imaging procedure (91%); had invasive ductal carcinoma (83.5%); histological grade 2 (51.4%); stage II (61.8%); and luminal subtype (67.9%). Among the 685 (91%) patients who underwent any radiologic staging, distant metastases (DMs) were detected in 32 (4.7%). In the univariate analyses, stage IIb and pathological lymph node involvement (pN1) showed a statistically significant association with the presence of DMs, versus only a trend for triple negative and human epidermal growth factor receptor 2 (Her2) positive subtype. In an exploratory analysis performed in this same subgroup, when unfavorable biology (triple negative or Her2 positive) was present, patients had a DM rate of 14.4%, one of the highest reported at this stage of the disease. CONCLUSION: Early breast cancer has a low prevalence of DM at the initial evaluation, and systemic staging of asymptomatic, unselected patients is not warranted as a routine practice. However, we have identified subgroups of patients to whom a full staging could be indicated.

OBJETIVO: Metástases são de ocorrência rara no câncer de mama precoce, e as diretrizes internacionais não recomendam o estadiamento sistêmico de rotina para pacientes assintomáticos. Apesar disso, exames de imagem continuam sendo largamente empregados na prática clínica. O objetivo do presente estudo é avaliar o valor do estadiamento por imagem no câncer de mama precoce. MéTODOS: Análise retrospectiva de pacientes recém-diagnosticados com câncer de mama. Foram registrados os dados clínicos dos pacientes, incluindo subtipo da neoplasia de mama, estadiamento, presença de sintomas no momento do diagnóstico e procedimentos de estadiamento. RESULTADOS: Um total de 753 pacientes foram incluídos, com idade média de 57 anos. Grande parte deles se submeteu a pelo menos um exame de imagem (91%); tinha carcinoma ductal invasivo (83,5%); grau histológico 2 (51,4%); estádio II (61,8%); e subtipo luminal (67,9%). Entre os 685 (91%) pacientes que realizaram algum exame de imagem, metástases à distância foram detectadas em 32 (4,7%). Na análise univariada, estádio IIb e acometimento linfonodal (pN1) tiveram uma associação estatisticamente significativa com a presença de metástase, enquanto os subtipos triplo negativo e receptor tipo 2 do fator de crescimento epidérmico humano (Her2) positivo demonstraram apenas uma tendência para a identificação de metástases. Na análise exploratória deste mesmo subgrupo, diante da presença de biologia desfavorável (triplo negativo e Her2 positivo), os pacientes apresentaram uma taxa de metástase à distância de 14,4%, uma das mais altas relatadas nesse estádio. CONCLUSãO: Neoplasia de mama precoce apresenta baixa baixa prevalência de metástase à distância no momento do diagnóstico, e o estadiamento sistêmico de rotina de pacientes assintomáticos e não selecionados não é justificável. Contudo, identificamos subgrupos de pacientes para os quais o estadiamento completo poderia ser indicado.

Genomic Landscape of Cell-Free DNA in Patients with Colorectal Cancer.

"Liquid biopsy" approaches analyzing cell-free DNA (cfDNA) from the blood of patients with cancer are increasingly utilized in clinical practice. However, it is not yet known whether cfDNA sequencing from large cohorts of patients with cancer can detect genomic alterations at frequencies similar to those observed by direct tumor sequencing, and whether this approach can generate novel insights. Here, we report next-generation sequencing data from cfDNA of 1,397 patients with colorectal cancer. Overall, frequencies of genomic alterations detected in cfDNA were comparable to those observed in three independent tissue-based colorectal cancer sequencing compendia. Our analysis also identified a novel cluster of extracellular domain (ECD) mutations in EGFR, mediating resistance by blocking binding of anti-EGFR antibodies. Patients with EGFR ECD mutations displayed striking tumor heterogeneity, with 91% harboring multiple distinct resistance alterations (range, 1-13; median, 4). These results suggest that cfDNA profiling can effectively define the genomic landscape of cancer and yield important biological insights.Significance: This study provides one of the first examples of how large-scale genomic profiling of cfDNA from patients with colorectal cancer can detect genomic alterations at frequencies comparable to those observed by direct tumor sequencing. Sequencing of cfDNA also generated insights into tumor heterogeneity and therapeutic resistance and identified novel EGFR ectodomain mutations. Cancer Discov; 8(2); 164-73. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 127.

Clinical impact of adjuvant radiation therapy delay after neoadjuvant chemotherapy in locally advanced breast cancer.

BACKGROUND: and Purpose: Post-operative radiation therapy (PORT) is usually indicated for patients with breast cancer (BC) after neoadjuvant chemotherapy (NAC) and surgery. However, the optimal timing to initiation of PORT is currently unknown. MATERIAL AND METHODS: We retrospectively evaluated data from patients with BC who received PORT after NAC and surgery at our institution from 2008 to 2014. Patients were categorized into three groups according to the time between surgery and PORT: <8 weeks, 8-16 weeks and >16 weeks. RESULTS: A total of 581 patients were included; 74% had clinical stage III. Forty-three patients started PORT within 8 weeks, 354 between 8 and 16 weeks and 184 beyond 16 weeks from surgery. With a median follow-up of 32 months, initiation of PORT up to 8 weeks after surgery was associated with better disease-free survival (DFS) (<8 weeks versus 8-16 weeks: HR 0.33; 95% CI 0.13-0.81; p = 0.02; <8 weeks versus >16 weeks: HR 0.38; 95% CI 0.15-0.96; p = 0.04) and better overall survival (OS) (<8 weeks versus 8-16 weeks: HR 0.22; 95% CI 0.05-0.90; p = 0.036; <8 weeks versus >16 weeks: HR 0.28; 95% CI 0.07-1.15; p = 0.08). CONCLUSION: PORT started up to 8 weeks after surgery was associated with better DFS and OS in locally-advanced BC patients submitted to NAC. Our findings suggest that early initiation of PORT is critically important for these patients. However, the low numbers of patients and events in this study prevent us from drawing firm conclusions.

Impacto da parada completa do tratamento de primeira-linha de pacientes com câncer colorretal metastático: revisão sistemática e meta-análise de estudos randomizados / The impact of complete chemotherapy stop on the overall survival of patients with advanced colorectal cancer in first line setting: a meta-analysis of randomized trials

Introdução: A duração da quimioterapia de primeira linha e seu impacto na sobrevida global dos pacientes com câncer colorretal metastático (CCRm) são controversos e, até o momento, estudos não conseguiram definir um claro padrão. Métodos: Revisão sistemática dos principais bancos de dados da literatura médica (MEDLINE, EMBASE e Cochrane Central Register of Controlled Trials), bem como trabalhos apresentados em congressos internacionais de oncologia (Sociedade Americana [ASCO] e Européia de Oncologia Clínica [ESMO]), em busca dos ensaios clínicos aleatorizados que compararam a sobrevida global (SG) dos pacientes com CCRm que receberam quimioterapia de primeira linha de forma contínua até progressão da doença versus parada completa de tratamento após um número fixo de ciclos de indução. O desfecho primário foi SG e os desfechos secundários incluíram desfechos de progressão do tipo tempo-para-evento, intervalo livre de quimioterapia, qualidade de vida e toxicidade. Uma meta-análise dos Hazard Ratios (HR) reportados para a SG foi realizada. Os estudos incluídos foram avaliados quanto às suas metodologias e análises de subgrupo foram realizadas quando heterogeneidades metodológicas foram encontradas. Análise de sensibilidade foi realizada quanto ao risco de viés, avaliado pela escala de Jadad, e quando teste de inconsistência de Higgins (I2) maior que 35% (heterogeneidade) foi encontrado. Resultados: A busca inicial resultou em 251 ensaios, dos quais 6 foram elegíveis e 5 forneceram dados suficientes para a meta-análise de SG (N = 3.061). A SG dos pacientes que receberam quimioterapia de forma contínua até progressão não foi estatisticamente diferente daqueles para quem foi oferecido parada completa de tratamento (HR = 0,93, IC95% = 0,84-1,03; I² = 12%; p = 0,15). Os resultados foram semelhantes quando analisados somente estudos classificados como de boa qualidade bem como nos subgrupos separados quanto ao momento de aleatorização (antes versus após terapia de...

Background: The impact of the duration of chemotherapy on the overall survival of patients with metastatic colorectal cancer (mCRC) is controversial and studies have failed to define a clear standard. Methods: We systematically searched medical literature databases (MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials), as well as oncology conferences proceedings (American Society of Clinical Oncology [ASCO] and European Society for Medical Oncology [ESMO] annual meetings) for randomized controlled trials (RCT) that compared the overall survival (OS) of mCRC patients who received first-line chemotherapy continuously until disease progression versus those who were offered complete treatment stop after a fixed number of cycles. The primary study endpoint was OS. The secondary endpoints were progression-free survival, chemotherapy-free interval, quality of life and rate of toxicities. A meta-analysis of reported Hazard Ratios for survival was performed. The studies included were evaluated for their methodologies and subgroup analyzes were performed when methodological heterogeneity was found. Sensitivity analysis was performed when relevant heterogeneity was found (defined as I²>35%). Results: We retrieved 251 trials, of which 6 were eligible and 5 were included in the pooled analysis of overall survival (N = 3,061). The overall survival between continuously delivered chemotherapy and complete stop was not statistically different (HR= 0.93, 95%IC = 0.84 to 1.03; p=0,15; I² = 12%). The results were similar when we analyzed separately only trials classified as high quality by Jadad scale and according to the following subgroups: trials that performing randomization before versus after induction therapy and according to the use of monoclonal antibody (yes or no). The median chemotherapy free interval in the complete-stop group was 3.9 months (3.6 - 4.3 months). Chemotherapy administered until progression was associated with more...