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BACKGROUND AND PURPOSE: The CardioSwitch-study demonstrated that patients with solid tumors who develop cardiotoxicity on capecitabine or 5-fluorouracil (5-FU) treatment can be safely switched to S-1, an alternative fluoropyrimidine (FP). In light of the European Medicines Agency approval of S-1 in metastatic colorectal cancer (mCRC), this analysis provides more detailed safety and efficacy information, and data regarding metastasectomy and/or local ablative therapy (LAT), on the mCRC patients from the original study. MATERIALS AND METHODS: This retrospective cohort study was conducted at 12 European centers. The primary endpoint was recurrence of cardiotoxicity after switch. For this analysis, safety data are reported for 78 mCRC patients from the CardioSwitch cohort (N = 200). Detailed efficacy and outcomes data were available for 66 mCRC patients. RESULTS: Data for the safety of S-1 in mCRC patients were similar to the original CardioSwitch cohort and that expected for FP-based treatment, with no new concerns. Recurrent cardiotoxicity (all grade 1) with S-1-based treatment occurred in 4/78 (5%) mCRC patients; all were able to complete FP treatment. Median progression-free survival from initiation of S-1-based treatment was 9.0 months and median overall survival 26.7 months. Metastasectomy and/or LAT was performed in 33/66 (50%) patients, and S-1 was successfully used in recommended neoadjuvant/conversion or adjuvant-like combination regimens and schedules as for standard FPs. INTERPRETATION: S-1 is a safe and effective FP alternative when mCRC patients are forced to discontinue 5-FU or capecitabine due to cardiotoxicity and can be safely used in the standard recommended regimens, settings, and schedules.
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Capecitabina , Cardiotoxicidad , Neoplasias Colorrectales , Combinación de Medicamentos , Fluorouracilo , Ácido Oxónico , Tegafur , Humanos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Tegafur/efectos adversos , Tegafur/administración & dosificación , Ácido Oxónico/administración & dosificación , Ácido Oxónico/efectos adversos , Ácido Oxónico/uso terapéutico , Masculino , Femenino , Persona de Mediana Edad , Anciano , Estudios Retrospectivos , Cardiotoxicidad/etiología , Capecitabina/efectos adversos , Capecitabina/administración & dosificación , Fluorouracilo/efectos adversos , Fluorouracilo/uso terapéutico , Fluorouracilo/administración & dosificación , Adulto , Anciano de 80 o más Años , Antimetabolitos Antineoplásicos/efectos adversos , Antimetabolitos Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
The primary tumor location (PTL) is associated with the phenotype, metastatic sites, mutations, and outcomes of metastatic colorectal cancer (mCRC) patients, but this has mostly been studied according to sidedness (right vs. left sided). We studied right colon vs. left colon vs. rectal PTL in a real-life study population (n = 1080). Health-related quality of life (HRQoL) was assessed multi-cross-sectionally with QLQ-C30, QLQ-CR29, EQ-5D, and 15D. A chi-square, Kaplan-Meier, and Cox regression were used to compare the groups. The PTL was in the right colon in 310 patients (29%), the left colon in 396 patients (37%), and the rectum in 375 patients (35%). The PTL was associated with distinct differences in metastatic sites during the disease trajectory. The resectability, conversion, and resection rates were lowest in the right colon, followed by the rectum, and were highest in the left colon. Overall survival was shortest for right colon compared with left colon or rectal PTL (median 21 vs. 35 vs. 36 months), with the same trends after metastasectomy or systemic therapy only. PTL also remained statistically significant in a multivariable model. The distribution of symptoms varied according to PTL, especially between the right colon (with general symptoms of metastases) and rectal PTL (with sexual- and bowel-related symptoms). mCRC, according to PTL, behaves differently regarding metastatic sites, resectability of the metastases, outcomes of treatment, and HRQoL.
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BRAF-V600E mutation (mt) is a strong negative prognostic and predictive biomarker in metastatic colorectal cancer (mCRC). Non-V600Emt, designated atypical BRAFmt (aBRAFmt) are rare, and little is known about their frequency, co-mutations and prognostic and predictive role. These were compared between mutational groups of mCRC patients collected from three Nordic population-based or real-world cohorts. Pathology of aBRAFmt was studied. The study included 1449 mCRC patients with 51 (3%) aBRAFmt, 182 (13%) BRAF-V600Emt, 456 (31%) RAS&BRAF wild-type (wt) and 760 (52%) RASmt tumours. aBRAFmt were seen in 2% of real-world and 4% of population-based cohorts. Twenty-six different aBRAFmt were detected, 11 (22%) class 2 (serrated adenocarcinoma in 2/9 tested), 32 (64%) class 3 (serrated in 15/25) and 4 (8%) unclassified. aBRAFmt patients were predominantly male, had more rectal primaries, less peritoneal metastases, deficient mismatch repair in one (2%), and better survival after metastasectomy (89% 5-year overall survival [OS]-rate) compared with BRAF-V600Emt. aBRAFmt and BRAF-V600Emt had poorer performance status and received fewer treatment lines than RAS&BRAFwt and RASmt. OS among aBRAFmt (median 14.4 months) was longer than for BRAF-V600Emt (11.2 months), but shorter than for RAS&BRAFwt (30.5 months) and RASmt (23.4 months). Addition of bevacizumab trended for better OS for the aBRAFmt. Nine patients with aBRAFmt received cetuximab/panitumumab without response. aBRAFmt represents a distinct subgroup differing from other RAS/BRAF groups, with serrated adenocarcinoma in only half. OS for patients with aBRAFmt tumours was slightly better than for BRAF-V600Emt, but worse than for RASmt and RAS&BRAFwt. aBRAFmt should not be a contraindication for metastasectomy.
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Adenocarcinoma , Neoplasias del Colon , Neoplasias Colorrectales , Neoplasias del Recto , Humanos , Masculino , Femenino , Proteínas Proto-Oncogénicas B-raf/genética , Neoplasias Colorrectales/patología , MutaciónRESUMEN
Older adults are underrepresented in metastatic colorectal cancer (mCRC) studies and thus may not receive optimal treatment, especially not metastasectomies. The prospective Finnish real-life RAXO-study included 1086 any organ mCRC patients. We assessed repeated centralized resectability, overall survival (OS), and quality of life (QoL) using 15D and EORTC QLQ-C30/CR29. Older adults (>75 years; n = 181, 17%) had worse ECOG performance status than adults (<75 years, n = 905, 83%), and their metastases were less likely upfront resectable. The local hospitals underestimated resectability in 48% of older adults and in 34% of adults compared with the centralized multidisciplinary team (MDT) evaluation (p < 0.001). The older adults compared with adults were less likely to undergo curative-intent R0/1-resection (19% vs. 32%), but when resection was achieved, OS was not significantly different (HR 1.54 [CI 95% 0.9-2.6]; 5-year OS-rate 58% vs. 67%). 'Systemic therapy only' patients had no age-related survival differences. QoL was similar in older adults and adults during curative treatment phase (15D 0.882-0.959/0.872-0.907 [scale 0-1]; GHS 62-94/68-79 [scale 0-100], respectively). Complete curative-intent resection of mCRC leads to excellent survival and QoL even in older adults. Older adults with mCRC should be actively evaluated by a specialized MDT and offered surgical or local ablative treatment whenever possible.
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Neoplasias Colorrectales , Neoplasias Hepáticas , Humanos , Proteínas Proto-Oncogénicas B-raf/genética , Estudios Prospectivos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/cirugía , Neoplasias Colorrectales/patología , Hepatectomía , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/cirugía , Neoplasias Hepáticas/secundario , Mutación , Proteínas Proto-Oncogénicas p21(ras)RESUMEN
BACKGROUND: Outcomes after metastasectomy for metastatic colorectal cancer (mCRC) vary with RAS and BRAF mutational status, but their effects on resectability and conversion rates have not been extensively studied. METHODS: This substudy of the prospective RAXO trial included 906 patients recruited between 2011 and 2018. We evaluated repeated centralised resectability assessment, conversion/resection rates and overall survival (OS), according to RAS and BRAF status. RESULTS: Patients included 289 with RAS and BRAF wild-type (RAS and BRAFwt), 529 with RAS mutated (RASmt) and 88 with BRAF mutated (BRAFmt) mCRC. Metastatic prevalence varied between the RAS and BRAFwt/RASmt/BRAFmt groups, for liver (78%/74%/61%), lung (24%/35%/28%) and peritoneal (15%/15%/32%) metastases, respectively. Upfront resectability (32%/29%/15%), conversion (16%/13%/7%) and resection/local ablative therapy (LAT) rates (45%/37%/17%) varied for RASa and BRAFwt/RASmt/BRAFmt, respectively. Median OS for patients treated with resection/LAT (n = 342) was 83/69/30 months, with 5-year OS-rates of 67%/60%/24%, while systemic therapy-only patients (n = 564) had OS of 29/21/15 months with 5-year OS-rates of 11%/6%/2% in RAS and BRAFwt/RASmt/BRAFmt, respectively. Resection/LAT was associated with improved OS in all subgroups. CONCLUSIONS: There were significant differences in resectability, conversion and resection/LAT rates according to RAS and BRAF status. OS was also significantly longer for RAS and BRAFwt versus either mutant. Patients only receiving systemic therapy had poorer long-term survival, with variation according to molecular status. CLINICAL TRIAL REGISTRATION: NCT01531621/EudraCT2011-003158-24.
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Neoplasias del Colon , Neoplasias Colorrectales , Metastasectomía , Neoplasias del Recto , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/cirugía , Humanos , Mutación , Estudios Prospectivos , Proteínas Proto-Oncogénicas B-raf/genéticaRESUMEN
Metastasectomy and/or local ablative therapy in metastatic colorectal cancer (mCRC) patients often provide long-term survival. Health-related quality of life (HRQoL) data in curatively treated mCRC are limited. In the RAXO-study that evaluated repeated resectability, a multi-cross-sectional HRQoL substudy with 15D, EQ-5D-3L, QLQ-C30, and QLQ-CR29 questionnaires was conducted. Mean values of patients in different treatment groups were compared with age- and gender-standardized general Finnish populations. The questionnaire completion rate was 444/477 patients (93%, 1751 questionnaires). Mean HRQoL was 0.89−0.91 with the 15D, 0.85−0.87 with the EQ-5D, 68−80 with the EQ-5D-VAS, and 68−79 for global health status during curative treatment phases, with improvements in the remission phase (disease-free >18 months). In the remission phase, mean EQ-5D and 15D scores were similar to the general population. HRQoL remained stable during first- to later-line treatments, when the aim was no longer cure, and declined notably when tumour-controlling therapy was no longer meaningful. The symptom burden affecting mCRC survivors' well-being included insomnia, impotence, urinary frequency, and fatigue. Symptom burden was lower after treatment and slightly higher, though stable, through all phases of systemic therapy. HRQoL was high in curative treatment phases, further emphasizing the strategy of metastasectomy in mCRC when clinically meaningful.
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BACKGROUND: KRAS mutations, present in over 40% of metastatic colorectal cancer (mCRC), are negative predictive factors for anti-EGFR therapy. Mutations in KRAS-G12C have a cysteine residue for which drugs have been developed. Published data on this specific mutation are conflicting; thus, we studied the frequency and clinical characteristics in a real-world and population-based setting. METHODS: Patients from three Nordic population-based cohorts and the real-life RAXO-study were combined. RAS and BRAF tests were performed in routine healthcare, except for one cohort. The dataset consisted of 2,559 patients, of which 1,871 could be accurately classified as KRAS, NRAS, and BRAF-V600E. Demographics, treatments, and outcomes were compared using logistic regression. Overall survival (OS) was estimated with Kaplan-Meier, and differences were compared using Cox regression, adjusted for baseline factors. RESULTS: The KRAS-G12C frequency was 2%-4% of all tested in the seven cohorts (mean 3%) and 4%-8% of KRAS mutated tumors in the cohorts (mean 7%). Metastasectomies and ablations were performed more often (38% vs. 28%, p = 0.040), and bevacizumab was added more often (any line 74% vs. 59%, p = 0.007) for patients with KRAS-G12C- vs. other KRAS-mutated tumors, whereas chemotherapy was given to similar proportions. OS did not differ according to KRAS mutation, neither overall (adjusted hazard ratio (HR) 1.03; 95% CI 0.74-1.42, reference KRAS-G12C) nor within treatment groups defined as "systemic chemotherapy, alone or with biologics", "metastasectomy and/or ablations", or "best supportive care", RAS and BRAF wild-type tumors (n = 548) differed similarly to KRAS-G12C, as to other KRAS- or NRAS-mutated (n = 66) tumors. CONCLUSIONS: In these real-life and population-based cohorts, there were no significant differences in patient characteristics and outcomes between patients with KRAS-G12C tumors and those with other KRAS mutations. This contrasts with the results of most previous studies claiming differences in many aspects, often with worse outcomes for those with a KRAS-G12C mutation, although not consistent. When specific drugs are developed, as for this mutation, differences in outcome will hopefully emerge.
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BACKGROUND: Resection of colorectal cancer (CRC) metastases provides good survival but is probably underused in real-world practice. METHODS: A prospective Finnish nationwide study enrolled treatable metastatic CRC patients. The intervention was the assessment of resectability upfront and twice during first-line therapy by the multidisciplinary team (MDT) at Helsinki tertiary referral centre. The primary outcome was resection rates and survival. FINDINGS: In 2012-2018, 1086 patients were included. Median follow-up was 58 months. Multiple metastatic sites were present in 500 (46%) patients at baseline and in 820 (76%) during disease trajectory. In MDT assessments, 447 (41%) were classified as resectable, 310 (29%) upfront and 137 (18%) after conversion therapy. Six-hundred and ninety curative intent resections or local ablative therapies (LAT) were performed in 399 patients (89% of 447 resectable). Multiple metastasectomies for multisite or later developing metastases were performed in 148 (37%) patients. Overall, 414 liver, 112 lung, 57 peritoneal, and 107 other metastasectomies were performed. Median OS was 80·4 months in R0/1-resected (HR 0·15; CI95% 0·12-0·19), 39·1 months in R2-resected/LAT (0·39; 0·29-0·53) patients, and 20·8 months in patients treated with "systemic therapy alone" (reference), with 5-year OS rates of 66%, 40%, and 6%, respectively. INTERPRETATION: Repeated centralized MDT assessment in real-world metastatic CRC patients generates high resectability (41%) and resection rates (37%) with impressive survival, even when multisite metastases are present or develop later. FUNDING: The funders had no role in the study design, analysis, and interpretation of the data or writing of this report.
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BACKGROUND: Gastric cancer (GC) is the third most common cause of cancer death. Intestinal type GC is a molecularly diverse disease. Formins control cytoskeletal processes and have been implicated in the progression of many cancers. Their clinical significance in GC remains unclear. Here, we characterize the expression of formin proteins FHOD1 and FMNL1 in intestinal GC tissue samples and investigate their association with clinical parameters, GC molecular subtypes and intratumoral T lymphocytes. METHODS: The prognostic significance of FHOD1 and FMNL1 mRNA expression was studied with Kaplan-Meier analyses in an online database. The expression of FHOD1 and FMNL1 proteins was characterized in GC cells, and in non-neoplastic and malignant tissues utilizing tumor microarrays of intestinal GC representing different molecular subtypes. FHOD1 and FMNL1 expression was correlated with clinical parameters, molecular features and T lymphocyte infiltration. Immunohistochemical expression of neither formin correlated with survival. RESULTS: Kaplan-Meier analysis associated high FHOD1 and FMNL1 mRNA expression with reduced overall survival (OS). Characterization of FHOD1 and FMNL1 in GC cells showed cytoplasmic expression along the actin filaments. Similar pattern was recapitulated in GC tissue samples. Elevated FMNL1 was associated with larger tumor size and higher disease stage. Downregulation of FHOD1 associated with TP53-mutated GC tumors. Tumor cell FHOD1 expression strongly correlated with high numbers of tumor-infiltrating CD8 + lymphocytes. CONCLUSIONS: FHOD1 and FMNL1 proteins are expressed in the tumor cells of intestinal GC and significantly associate with clinical parameters without direct prognostic significance. FHOD1 correlates with high intratumoral CD8 + T lymphocyte infiltration in this cohort.
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Linfocitos Infiltrantes de Tumor/metabolismo , Neoplasias Gástricas/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Femenino , Proteínas Fetales/metabolismo , Finlandia , Forminas/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/patología , Análisis de SupervivenciaRESUMEN
While host immune response is likely to be important for the prognosis of gastric cancer patients, detailed information on the T lymphocyte infiltration in different gastric cancer subtypes is lacking. Here, we studied the presence of CD3, CD8, and FOXP3 (Forkhead box p3) expressing T lymphocytes in a retrospective cohort of 190 intestinal gastric and gastroesophageal adenocarcinomas. The cancers represented four distinct molecular subtypes: Epstein-Barr virus-positive (EBV+), mismatch-repair-deficient (MMR-D), aberrant TP53, and the "other" subtype. The absolute numbers of CD3+, CD8+, and FOXP3+ T lymphocytes were analyzed in relation with these molecular subtypes and selected clinicopathological parameters. Overall, there was a large variation in the amount of infiltrating T lymphocyte in all molecular subtypes. Among the subtypes, EBV+ cancers differed from the other subtypes in increased lymphocyte infiltration and high CD8+/FOXP3+ ratio. While the TP53 aberrant subtype did not differ in the absolute amount of T lymphocyte, the ratio of CD8+/FOXP3+ and CD3+/FOXP3+ cells was highest in this subtype, possibly reflecting immunosuppression associated with genomic instability. Increased CD3+ and CD8+ T lymphocyte infiltrates were associated with better survival, and remained as independent prognostic factors in a multivariate analysis. This study is the first to investigate lymphocytic infiltration within four molecular subtypes of intestinal-type gastric cancer in a European cohort. The results provide an important addition to the current knowledge of T lymphocyte-dependent immune response in gastric cancer and its prognostic significance.
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Adenocarcinoma/inmunología , Adenocarcinoma/patología , Biomarcadores de Tumor/metabolismo , Linfocitos Infiltrantes de Tumor/metabolismo , Neoplasias Gástricas/inmunología , Neoplasias Gástricas/patología , Adenocarcinoma/metabolismo , Adenocarcinoma/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Esofágicas/inmunología , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/patología , Femenino , Estudios de Seguimiento , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Estudios Retrospectivos , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/mortalidad , Análisis de Supervivencia , Análisis de Matrices TisularesRESUMEN
PURPOSE: The aim of this retrospective single-center analysis was to evaluate the feasibility of fluorine-18 fluorodeoxyglucose (FDG)-PET imaging in evaluating metabolic response of preoperative chemotherapy in the treatment of locally advanced operable gastroesophageal adenocarcinoma and to investigate the association between histopathologic and FDG-PET response and overall survival. METHODS: Patients with locally advanced adenocarcinoma of distal esophagus, gastroesophageal junction or stomach were assessed for the study during 2008-2012. After evaluation with endoscopy, computed tomography and FDG-PET, patients with clinical stage II or III disease were assigned for perioperative EOX (epirubicin-oxaliplatin-capecitabine) treatment targeted at three cycles both pre- and postoperatively, if possible. Metabolic response was evaluated by repeated FDG-PET during or right after the second chemotherapy cycle. Becker tumor regression grade (TRG) was used to evaluate histopathologic response. For statistical purposes, the clinically significant cut-off for tumor maximum standardized uptake value (SUVmax) change (SUVδ%) was set at -35%. RESULTS: 54 patients were included in the study. 53 PET images were obtained before chemotherapy, 11 (21%) of those were PET negative. A major metabolic response was detected in 19 patients and major histopathologic response in 14 patients. No statistically significant association was observed between SUVδ% and histopathological responses. Median overall survival (OS) time of the patients was 49.9 months. No association between OS and PET response was found in our study. The administration of all six cycles of perioperative EOX was associated with improved OS. CONCLUSIONS: Follow-up PET during or right after second preoperative chemotherapy cycle did not assist in identifying patients with favorable histopathological response or OS.
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Adenocarcinoma/patología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Esofágicas/patología , Fluorodesoxiglucosa F18/metabolismo , Atención Perioperativa , Tomografía de Emisión de Positrones/métodos , Neoplasias Gástricas/patología , Adenocarcinoma/diagnóstico por imagen , Adenocarcinoma/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Capecitabina/administración & dosificación , Epirrubicina/administración & dosificación , Neoplasias Esofágicas/diagnóstico por imagen , Neoplasias Esofágicas/tratamiento farmacológico , Unión Esofagogástrica , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Oxaliplatino/administración & dosificación , Pronóstico , Radiofármacos/metabolismo , Estudios Retrospectivos , Neoplasias Gástricas/diagnóstico por imagen , Neoplasias Gástricas/tratamiento farmacológico , Tasa de Supervivencia , Adulto JovenRESUMEN
Epidermal growth factor receptor (EGFR) gene copy number (GCN) increase is associated with a favorable anti-EGFR antibody treatment response in RAS wild-type metastatic colorectal cancer. However, there are limited and comparative data regarding the EGFR GCN in primary colorectal cancer tumors and corresponding metastases or the effect of anti-EGFR antibody treatment on EGFR GCN in recurrent disease. In addition, little is known about the potential EGFR GCN changes during anti-EGFR therapy in comparison with other treatment regimens. EGFR GCN was analyzed by EGFR immunohistochemistry-guided silver in situ hybridization in primary and corresponding recurrent local or metastatic tumors from 80 colorectal cancer patients. GCN levels were compared between KRAS wild-type patients having received anti-EGFR therapy and patients having received other forms of treatment after primary surgery. The EGFR GCN decrease between primary and recurrent tumors was more pronounced among the anti-EGFR-treated patients than among patients not treated with anti-EGFR therapy (P = .047). None of the patients experiencing an EGFR GCN increase of at least 1.0 between the primary and recurrent tumors were treated with anti-EGFR antibodies. When including only patients with distant metastases, an EGFR GCN decrease of at least 1.0 was more common among the anti-EGFR-treated patients than among patients not treated with anti-EGFR therapy (P = .028). Our results suggest that anti-EGFR antibody treatment is associated with EGFR GCN decrease between the primary and recurrent colorectal adenocarcinomas, whereas no GCN change is observed among patients receiving other forms of treatment after primary surgery.
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Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/genética , Antineoplásicos Inmunológicos/uso terapéutico , Cetuximab/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Dosificación de Gen , Panitumumab/uso terapéutico , Adenocarcinoma/inmunología , Adenocarcinoma/secundario , Adulto , Anciano , Anciano de 80 o más Años , Quimioterapia Adyuvante , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/patología , Regulación hacia Abajo , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Receptores ErbB/inmunología , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Masculino , Persona de Mediana Edad , Mutación , Recurrencia Local de Neoplasia , Proteínas Proto-Oncogénicas p21(ras)/genética , Estudios Retrospectivos , Factores de Tiempo , Resultado del TratamientoRESUMEN
Gastric cancer is traditionally divided into intestinal and diffuse histological subtypes, but recent molecular analyses have led to novel classification proposals based on genomic alterations. While the intestinal- and diffuse-type tumours are distinguishable from each other at the molecular level, intestinal-type tumours have more diverse molecular profile. The technology required for comprehensive molecular analysis is expensive and not applicable for routine clinical diagnostics. In this study, we have used immunohistochemistry and in situ hybridisation in molecular classification of gastric adenocarcinomas with an emphasis on the intestinal subtype. A tissue microarray consisting of 244 gastric adenocarcinomas was constructed, and the tumours were divided into four subgroups based on the presence of Epstein-Barr virus, TP53 aberrations and microsatellite instability. The intestinal- and diffuse-type tumours were separately examined. The distribution of EGFR and HER2 gene amplifications was studied in the intestinal-type tumours. Epstein-Barr virus positive intestinal-type tumours were more common in male patients (p = 0.035) and most often found in the gastric corpus (p = 0.011). The majority of the intestinal-type tumours with TP53 aberrations were proximally located (p = 0.010). All tumours with microsatellite instability showed intestinal-type histology (p = 0.017) and were associated with increased overall survival both in the univariate (p = 0.040) and multivariate analysis (p = 0.015). In conclusion, this study shows that gastric adenocarcinomas can be classified into biologically and clinically different subgroups by using a simple method also applicable for clinical diagnostics.
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Adenocarcinoma/patología , Biomarcadores de Tumor/análisis , Inmunohistoquímica , Neoplasias Gástricas/patología , Adenocarcinoma/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Inmunohistoquímica/métodos , Hibridación in Situ/métodos , Neoplasias Intestinales/metabolismo , Neoplasias Intestinales/patología , Masculino , Patología Clínica/métodos , Neoplasias Gástricas/metabolismoRESUMEN
PURPOSE: Treatment for patients with metastatic colorectal cancer is chemotherapy commonly combined with monoclonal antibodies against vascular endothelial growth factor (bevacizumab) or epidermal growth factor receptor (cetuximab or panitumumab), the efficacy of which has been proven in randomized controlled trials. The objective of the current retrospective study was to analyze the impact of targeted therapy, adverse events, and dose reduction on overall survival (OS) and metastasis resection rates. METHODS: A hospital-based electronic informatics center was used to gather clinical data and outcome information in a "real-life" setting in a single academic hospital. A total of 178 patients were included in 2010-2013. RESULTS: In patients whose tumors expressed the KRAS wild type, the longest median OS was observed with irinotecan-based chemotherapy combined with bevacizumab (38 months), or with cetuximab (41 months). In the KRAS-mutated group, the longest median OS was observed with oxaliplatin with or without bevacizumab (34 months). Beneficial liver metastasis resections were observed in 12 out of 20 patients. Patients with KRAS wild-type tumors who received cetuximab were the most likely to undergo surgery. Age was a negative predictor of OS. Patients whose chemotherapy dose was reduced to below 80% had lower OS compared to those remaining above 80%. Treatment delays in chemotherapy did not affect OS. Pulmonary embolism and infections were common but did not have an impact on OS. CONCLUSIONS: A hospital-based electronic informatics center provides comparable OS results, even though adverse events were frequently observed in the present study.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/terapia , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Colorrectales/genética , Registros Electrónicos de Salud , Femenino , Humanos , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida/efectos adversos , Terapia Molecular Dirigida/estadística & datos numéricos , Mutación , Metástasis de la Neoplasia , Proteínas Proto-Oncogénicas p21(ras)/genética , Recurrencia , Estudios Retrospectivos , Análisis de SupervivenciaRESUMEN
BACKGROUND: Most survival data in colorectal cancer (CRC) is derived from clinical trials or register-based studies. Hospital Biobanks, linked with hospital electronic records, could serve as a data-gathering method based on consecutively collected tumor samples. The aim of this Biobank study was to analyze survival of colorectal patients diagnosed and treated in a single-center university hospital over a period of 12 years, and to evaluate factors contributing to outcome. MATERIAL AND METHODS: A total of 1777 patients with CRC treated during 2001-2012 were identified from the Auria Biobank, Turku, Finland. Longitudinal clinical information was collected from various hospital electronic records and date and cause of death obtained from Statistics Finland. RESULTS: Cancer-specific, overall and disease-free survival was higher in patients diagnosed during 2004-2008 as compared with patients diagnosed in 2001-2003. Further improvement was not seen during years 2009-2012. Potential factors contributing to the improvement were introduction of multidisciplinary meetings, centralization of rectal cancer surgery, use of adjuvant chemotherapy and systematic preoperative radiotherapy of rectal cancer. The proportion of patients with stage I-IV CRC remained similar over the study period, but a marked decrease in non-metastatic rectal cancer with biopsy only (locally advanced disease) was observed. In stage I-III rectal cancer, Cox multivariate analysis suggested age, comorbidity, R1 resection, T staging and tumor grade as prognostic factors. In colon cancer, prognostic factors were age, comorbidity, gender and presence of lymph node metastases. CONCLUSIONS: Organizational changes in the treatment of CRC patients made since 2004 coincide with improved survival in CRC and a marked reduction in locally advanced rectal cancers. The clinical presentation of CRC has remained similar between 2001 and 2012.
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Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/terapia , Registros Electrónicos de Salud , Oncología Médica/tendencias , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Colorrectales/patología , Supervivencia sin Enfermedad , Femenino , Finlandia/epidemiología , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Modelos de Riesgos ProporcionalesRESUMEN
BACKGROUND: Parathyroid carcinoma (PC) is rare and diagnostically challenging. Reported outcomes are rather poor and the incidence might be increasing. MATERIAL AND METHODS: We performed a nationwide study on all cases (n= 32) diagnosed in 2000-2011 in Finland, and compared clinical and histopathological characteristics and outcome to atypical parathyroid (APA; n= 28) and parathyroid adenomas (PA; n= 72). The incidence in years 1955-1999 was compared to that in 2000-2013. RESULTS: Preoperatively, calcium and parathyroid hormone concentrations were higher in PC compared to APA and PA (1.76, 1.56 and 1.44 mmol/l, p < .001; and 989, 355 and 160 µmol/l, p < .001, respectively). Calcium was ≤1.77 mmol/l for all PAs. Hospitalization (44% vs. 22% and 3%, respectively, p = .01), renal (50% vs. 48% vs. 22%, respectively, p = .01) and bone (47% vs. 15% vs. 38%, respectively p = .002) manifestations were more common. PC and APA tumors were larger than PA (p < .001). Histopathological characteristics of PC compared to PA are increased mitotic activity (p= .001), chief cells (p = .003), diffuse growth pattern (p < .001), higher Ki67 (p< .001) and negative parafibromin (p < .001). One PC (1/18) and one APA (1/16) patient had a CDC73 mutation. After 6.7 (2-13.9) years of follow-up, 9.4% of PC had residual, 21% recurrent disease and 12.5% died of disease. Overall mortality did not differ between subgroups (p = .094). Recurrent PC was characterized by vascular invasion, lymph node metastases, high mitotic activity, necrosis and negative parafibromin. Incidence increased from 1.42 (range 0.52-2.14) to 7.14 (range 3.42-10.38)/10.000.000/years; (p < .001). CONCLUSIONS: PC associates with severe primary hyperparathyroidism and must be suspected if calcium ≥1.77 mmol/l. The prevalence of CDC73 germline mutations in PC and APA in Finland is 6%. PC has distinct histopathological characteristics and its incidence has increased over the past decades.
Asunto(s)
Recurrencia Local de Neoplasia/epidemiología , Neoplasias de las Paratiroides/epidemiología , Paratiroidectomía , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Femenino , Estudios de Seguimiento , Mutación de Línea Germinal , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Incidencia , Metástasis Linfática , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/cirugía , Neoplasias de las Paratiroides/patología , Neoplasias de las Paratiroides/cirugía , Pronóstico , Estudios Retrospectivos , Proteínas Supresoras de Tumor/genética , Adulto JovenRESUMEN
Anti-EGFR antibodies are used for the treatment of RAS wild type metastatic colorectal cancer. We previously showed that EGFR gene copy number (GCN) predicts response to anti-EGFR therapy in KRAS exon 2 wild type metastatic colorectal cancer. The aim of our study was to analyse the predictive role of EGFR GCN in RAS/BRAF/PIK3CA wild type metastatic colorectal cancer. The material included 102 patients with KRAS exon 2 wild type metastatic colorectal cancer treated with anti-EGFR ± cytotoxic therapy. Next generation sequencing was used for KRAS, NRAS, BRAF and PIK3CA gene mutation analyses. EGFR GCN was analysed by EGFR immunohistochemistry guided automated silver in situ hybridisation. Increased EGFR GCN (≥4.0) predicted a better response and prolonged progression free survival in anti-EGFR treated RAS/BRAF/PIK3CA wild type patients (Log-rank test, p = 0.0004). In contrast, survival of RAS/BRAF/PIK3CA wild type, EGFR GCN below 4.0 patients did not differ from patients with mutant RAS, BRAF or PIK3CA. Our study indicates that EGFR GCN predicts anti-EGFR treatment efficacy in patients with RAS/BRAF/PIK3CA wt metastatic CRC. Tumours with EGFR GCN below 4.0 appear to be as refractory to anti-EGFR treatment as tumours with mutation in any of the RAS/RAF/PIK3CA pathway genes.
Asunto(s)
Adenocarcinoma/genética , Anticuerpos Monoclonales/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Cetuximab/uso terapéutico , Neoplasias Colorrectales/genética , Genes ras , Terapia Molecular Dirigida , Fosfatidilinositol 3-Quinasas/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas B-raf/genética , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/secundario , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/administración & dosificación , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Cetuximab/administración & dosificación , Cetuximab/farmacología , Fosfatidilinositol 3-Quinasa Clase I , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Supervivencia sin Enfermedad , Resistencia a Antineoplásicos/genética , Receptores ErbB , Femenino , Fluorouracilo/administración & dosificación , Estudios de Seguimiento , Dosificación de Gen , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Irinotecán , Masculino , Persona de Mediana Edad , Mutación , Panitumumab , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/farmacologíaRESUMEN
Adjuvant chemotherapy for 6 months following curative resection of colorectal cancer (CRC) reduces recurrence risk and improves survival in lymph node positive, stage III disease. In stage II CRC the benefit of adjuvant chemotherapy is smaller and only recommended if high risk prognostic factors are present. Microsatellite instability in stage II CRC is associated with a favourable prognosis and when present adjuvant chemotherapy is not needed. Adjuvant chemotherapy improves disease outcome also in elderly patients (≥ 70 years) with stage III CRC, but is not recommended in stage II disease. Adjuvant chemotherapy should be started within 8 weeks following surgery.