Atypical (non-V600E) BRAF mutations in metastatic colorectal cancer in population and real-world cohorts.

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.

Detailed analysis of metastatic colorectal cancer patients who developed cardiotoxicity on another fluoropyrimidine and switched to S-1 treatment (subgroup analysis of the CardioSwitch-study).

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.

Resectability, conversion, metastasectomy and outcome according to RAS and BRAF status for metastatic colorectal cancer in the prospective RAXO study.

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.

Impact of Primary Tumor Location on Demographics, Resectability, Outcomes, and Quality of Life in Finnish Metastatic Colorectal Cancer Patients (Subgroup Analysis of the RAXO Study).

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.

Resectability, Resections, Survival Outcomes, and Quality of Life in Older Adult Patients with Metastatic Colorectal Cancer (the RAXO-Study).

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.

Retrospective single-center study on elderly patients with glioblastoma between 2014 and 2018 evaluating the effect of age and performance status on survival.

Background: Incidence of glioblastoma (GBM) increases with age and the prognosis is worse among the elderly. This was shown in a Finnish population-based register study evaluating GBM patients diagnosed between 2000 and 2013. The median overall survival (OS) was poor among the elderly (4.5 months), despite the OS increase during that period. We conducted a study to see if the OS has increased in our hospital area with current therapies. Methods: One hundred and ninety-eight patients over 65 years at the time of diagnosis, with malignant glioma diagnosed January 1, 2014 to December 31, 2018 at the Helsinki Comprehensive Cancer Center were included. In addition to grade IV gliomas, grade III gliomas with nonmutated R132HIDH1 and only radiographically diagnosed gliomas were included. The demographics and treatment data were collected with performance status evaluated retrospectively. The Kaplan-Meier method and the multivariate Cox proportional hazard model were used for the statistical analysis. Results: One hundred and seventy-seven patients with grade IV glioma, 6 with grade III glioma with nonmutated IDH1 and 15 radiologically diagnosed patients were included. One hundred and sixteen patients received chemoradiation, 59 only radiotherapy, 3 only temozolomide, and 27 patients did not receive oncological treatments. In the age group 65-70 years the OS was 9.95 months, 70-75 years 10.12 months, and >75 years 5.54 months. Lower WHO status correlated with longer survival independently of the age of the patient. Also methylated O(6)-methylguanine-DNA-methyltransferase and tumor resection correlated with better survival. Conclusions: The performance status of elderly patients is the most important prognostic factor. When choosing treatment protocols for patients in this age group, the performance status not calendar age should be considered.

KRAS-G12C Mutation in One Real-Life and Three Population-Based Nordic Cohorts of Metastatic Colorectal Cancer.

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.

Health-Related Quality of Life in Metastatic Colorectal Cancer Patients Treated with Curative Resection and/or Local Ablative Therapy or Systemic Therapy in the Finnish RAXO-Study.

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.

Repeated centralized multidisciplinary team assessment of resectability, clinical behavior, and outcomes in 1086 Finnish metastatic colorectal cancer patients (RAXO): A nationwide prospective intervention study.

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.

Effect of Adjuvant Trastuzumab for a Duration of 9 Weeks vs 1 Year With Concomitant Chemotherapy for Early Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: The SOLD Randomized Clinical Trial.

Importance: Trastuzumab plus chemotherapy is the standard adjuvant treatment for patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer. While the standard duration of trastuzumab treatment is 12 months, the benefits and harms of trastuzumab continued beyond the chemotherapy are unclear. Objective: To evaluate the efficacy and safety of adjuvant trastuzumab continued beyond chemotherapy in women treated with up-front chemotherapy containing a taxane and trastuzumab. Design, Setting, and Participants: Open-label, randomized (1:1) clinical trial including women with HER2-positive breast cancer. Chemotherapy was identical in the 2 groups, consisting of 3 cycles of 3-weekly docetaxel (either 80 or 100 mg/m2) plus trastuzumab for 9 weeks, followed by 3 cycles of fluorouracil, epirubicin, and cyclophosphamide. Thereafter, no trastuzumab was administered in the 9-week group, whereas controls received trastuzumab to complete 1 year of administration. Disease-free survival (DFS) was compared between the groups using a Cox model and the noninferiority approach. The estimated sample size was 2168 patients (1-sided testing, with a relative noninferiority margin of 1.3). From January 3, 2008, to December 16, 2014, 2176 patients were accrued from 7 countries. Intervention: Docetaxel plus trastuzumab for 9 weeks, followed by 3 cycles of fluorouracil, epirubicin, and cyclophosphamide in both groups. Controls continued trastuzumab to 1 year. Main Outcomes and Measures: The primary objective was DFS; secondary objectives included distant disease-free survival, overall survival, cardiac DFS, and safety. Results: In the 2174 women analyzed, median age was 56 (interquartile range [IQR], 48-64) years. The median follow-up was 5.2 (IQR, 3.8-6.7) years. Noninferiority of the 9-week treatment could not be demonstrated for DFS (hazard ratio, 1.39; 2-sided 90% CI, 1.12-1.72). Distant disease-free survival and overall survival did not differ substantially between the groups. Thirty-six (3%) and 21 (2%) patients in the 1-year and the 9-week groups, respectively, had cardiac failure; the left ventricle ejection fraction was better maintained in the 9-week group. An interaction was detected between the docetaxel dose and DFS; patients in the 9-week group treated with 80 mg/m2 had inferior and those treated with 100 mg/m2 had similar DFS as patients in the 1-year group. Conclusions and Relevance: Nine weeks of trastuzumab was not noninferior to 1 year of trastuzumab when given with similar chemotherapy. Cardiac safety was better in the 9-week group. The docetaxel dosing with trastuzumab requires further study. Trial Registration: ClinicalTrials.gov Identifier: NCT00593697.

First-day iodine kinetics is useful for individualizing radiation safety precautions for thyroid carcinoma patients.

OBJECTIVE: There is considerable variation in the national regulations of different countries for the release of patients from hospitals after radioiodine therapy. Individual variations make these practices, when based on the worst case scenarios, too restrictive for the majority of patients. However, there are cases in which strict rules are needed to comply with the dose limits to other individuals, especially children. We have developed a method to individualize radiation safety precautions. MATERIALS AND METHODS: Twenty-three patients with differentiated thyroid carcinoma were included in the study. Four weeks after thyroidectomy, 1.1-3.7 GBq of radioiodine was administered and iodine kinetics were followed with external measurements until hospital discharge. The absorbed dose at the wrist holder was measured with thermoluminescence dosimetry (TLD) during hospital stay and after hospital discharge for up to 1 week. The TLD results were compared with the iodine kinetics. The dose to other individuals was estimated with extra TLDs located both on the patient's bed and given to family members. The kinetics data were fitted in both monoexponential and biexponential models and both for the full measurement period (down to the residual activity level<400 MBq) and for the first 24 h after radioiodine administration. RESULTS: The biexponential model was capable of predicting the cumulated dose up to 1 week for both the longer and the shorter measured data set. The occupancy factors both for a person sleeping on the same bed and for a person living in the same apartment with the patient were in agreement with the recommended occupancy factor values of the American Thyroid Association. From these findings it is possible to individualize radiation safety precautions by taking into account the iodine pharmacokinetics and living conditions of a patient. CONCLUSION: By measuring the activity content within the body for the first 24 h after radioiodine administration it is possible to individualize radiation safety precautions for thyroid carcinoma patients.

Erythrocyte concentrations of metabolites or cumulative doses of 6-mercaptopurine and methotrexate do not predict liver changes in children treated for acute lymphoblastic leukemia.

BACKGROUND: During therapy consisting of 6MP and MTX, metabolites accumulate in the erythrocytes. The erythrocyte levels of metabolites reflect the intensity of therapy. Whether they are associated with hepatotoxicity manifested as histological liver changes is not known. We studied the association of the metabolites and cumulative doses of 6MP and MTX with histological liver disease. METHODS: Serial measurements of E-TGN, E-MTX, and ALT during maintenance therapy were performed and cumulative doses of 6MP and MTX were calculated as g/m2 in 16 children with ALL. Each subject underwent a percutaneous liver biopsy at the end of therapy to screen for histological liver disease. RESULTS: No differences in E-TGN, E-MTX, or cumulative doses of 6MP or MTX were detected in the children with ALL with liver fibrosis compared to those without fibrosis, or in the children with less liver fatty change compared to those with more fatty change. Serum median ALT levels correlated significantly positively with cumulative doses of 6MP during therapy (rS = 0.527, P = 0.036), but not with cumulative doses of MTX, or E-TGN, or E-MTX. CONCLUSIONS: Erythrocyte levels of the metabolites or the cumulative doses of 6MP and MTX do not predict histological liver disease in children treated for ALL.

Iron overload in children who are treated for acute lymphoblastic leukemia estimated by liver siderosis and serum iron parameters.

OBJECTIVE: To evaluate a secondary liver iron overload and its fate in children who are treated conventionally for acute lymphoblastic leukemia and to assess whether serum soluble transferrin receptor (sTfR) is useful in detecting iron load. METHODS: Liver siderosis was estimated histologically from liver biopsy specimens of 30 children (aged 2.6-17.6 years) close to or at the end of therapy using total iron score (TIS). Serum iron parameters and sTfR were measured at the same time and in 22 patients 1 to 3 years after therapy. RESULTS: In 19 (63%) of 30 patients, liver TIS was >15, indicating at least moderate iron overload. Serum ferritin, iron, and transferrin iron saturation levels were highest and transferrin level lowest in the patients with the highest liver iron content. Serum sTfR levels did not differ significantly between the patients with varying amounts of liver iron. TIS correlated most significantly positively with serum ferritin (r(S) = 0.899), transferrin iron saturation (r(S) = 0.764), and the amount of transfused red blood cells (r(S) = 0.783). Serum iron parameters normalized in most patients during the follow-up. In 3 (14%) of 22 patients, serum ferritin level remained high (>1000 microg/L). CONCLUSIONS: Long-term iron overload is detected in at least 14% of children after therapy for acute lymphoblastic leukemia. Serum sTfR is an inappropriate marker for liver iron overload, whereas ferritin seems to be the most useful serologic marker for it.

Liver histology after current intensified therapy for childhood acute lymphoblastic leukemia: microvesicular fatty change and siderosis are the main findings.

BACKGROUND: During modern intensified therapy for childhood acute lymphoblastic leukemia (ALL) serum liver enzymes reach fairly high levels. Since no recent data on liver histopathology after therapy are available, we conducted a study of the subject. PROCEDURE: Liver biopsy specimens were evaluated and serum liver function tests and lipid profiles measured from 27 consecutive children, aged 3.5-17.6 years, treated according to the regimens for standard (SR) and intermediate risk (IR) ALL. RESULTS: None of the patients had entirely normal liver histology. Fatty infiltration was detected in 25 out of 27 (93%) and siderosis in 19 out of 27 patients (70%). Fourteen (52%) had both. Three (11%) also had mild portal and/or periportal fibrosis in addition to fatty change and siderosis. Fatty change was mainly microvesicular. Siderosis was in most cases grade II/IV to III/IV (in 16/19 or 84%). No hepatitis or cirrhosis was found. Serum total and LDL-cholesterol levels were higher in the patients with fibrosis than in the patients with fatty change (P = 0.036, P = 0.042) or with siderosis +/- fatty change (P = 0.036, P = 0.042). In serial ALT measurements a value of 300 U/L or more was oftener reached in the fibrosis than in the fatty change or siderosis groups (in 33 vs. in 12 or in 4% of the measurements, respectively, P = 0.014, in Kruskall-Wallis test). CONCLUSIONS: Microvesicular fatty change and siderosis are the main liver findings after current therapy for childhood ALL. Fibrosis occurs rarely. High values in serial serum ALT measurements repeatedly or a disturbed serum lipid profile may facilitate decisions about the need for a liver biopsy.