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Net Change of Mutational Load

Plasma-Select Sequence Mutations Gene List

Purpose:Mutations in EGFR pathway genes are poor prognostic indicators in patients with metastatic colorectal cancer. Plasma analysis of cell-free DNA is a minimally invasive and highly sensitive method to detect somatic mutations in tumors.Experimental Design:Plasma samples collected from panitumumab-treated patients in the ASPECCT study at baseline and safety follow-up (SFU) were analyzed by a next-generation sequencing–based approach for extended RAS mutant allele frequency as a continuous variable and their association with clinical outcomes and the mutational prevalence of 63 cancer-related genes. The correlation between patient outcome and baseline mutational status of EGFR pathway genes was also examined.Results:Overall, 261 patients in the panitumumab arm had evaluable plasma samples. Patients with a higher RAS mutant allele frequency at baseline had worse clinical outcomes than those with a lower frequency (P < 0.001, Cox PH model); however, RAS mutations did not necessarily preclude patients from deriving benefits. The objective response rate (complete or partial response) was 10.8% for patients with baseline RAS mutations and 21.7% for those with BRAF mutations. The 63-gene panel analysis revealed an increase in tumor mutational burden from baseline to SFU (P < 0.001, Wilcoxon signed rank test). Baseline mutations in EGFR pathway genes, when analyzed both categorically and continuously, were associated with shorter survival.Conclusions:When mutations in EGFR pathway genes were analyzed continuously, higher mutant allele frequency correlated with poorer outcomes. However, extended RAS mutation, by itself, did not preclude clinical responses to panitumumab in a monotherapy setting.

Introduction This study aimed to better understand panitumumab use in real-life clinical practice in first- and second-line treatment of metastatic colorectal cancer in five European countries. Methods This is a combined analysis of two observational, non-interventional prospective cohort studies, one of which was conducted in Germany and France, the other in Bulgaria, Czech Republic, and Hungary. The studies observed patients with wild-type [Kirsten] rat sarcoma viral oncogene homolog ([K]RAS/RAS) metastatic colorectal cancer (mCRC), who had been treated with panitumumab in combination with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) in the first line or with panitumumab combined with fluorouracil, leucovorin, and irinotecan (FOLFIRI) in the second line following fluoropyrimidine-based chemotherapy. The planned duration of observation was 12 months from the first dose of panitumumab. Results A total of 332 patients treated with panitumumab + FOLFOX in the first line and 94 patients treated with panitumumab + FOLFIRI in the second line were analyzed. The median number of panitumumab infusions was 10.0 in first-line FOLFOX patients and 11.5 in second-line FOLFIRI patients; the median duration of panitumumab exposure was 5.7 and 6.9 months, respectively. The unadjusted overall response rate (complete or partial response) in patients with available post-baseline response assessment (n = 290) was 51.7% in first-line FOLFOX and 44.9% in second-line FOLFIRI patients. In the first-line setting, resectability was achieved in 9.3%. Reported hospitalizations were mostly cancer-related visits such as scheduled anticancer treatment administrations, tumor assessment visits, or interventions. The majority of adverse drug reactions were skin disorders, with 75.3% in first-line FOLFOX patients and 72.3% in second-line FOLFIRI patients. Conclusion Overall, the study results show that treatment patterns, clinical efficacy, and the safety profile of panitumumab in routine clinical practice were comparable to those in randomized controlled trials. The relatively low skin toxicity rate could be attributed to increasing experience in managing panitumumab-associated rash and some degree of underreporting. Funding Amgen. Electronic supplementary material The online version of this article (10.1007/s12325-019-0874-6) contains supplementary material, which is available to authorized users.

Panitumumab is approved for RAS wild‐type metastatic colorectal cancer and was evaluated in Phase III (PRIME, NCT00364013) and Phase II (PEAK, NCT00819780) first‐line randomised studies. This retrospective analysis of these trials investigated efficacy and toxicity of panitumumab‐based maintenance after oxaliplatin discontinuation in RAS wild‐type patients. First‐line regimens were FOLFOX4 ± panitumumab in PRIME and mFOLFOX6 plus panitumumab or mFOLFOX6 plus bevacizumab in PEAK. Outcomes included median progression‐free survival (PFS) and overall survival (OS), from randomisation and oxaliplatin discontinuation, and toxicity. Overall, median duration of panitumumab plus 5‐fluorouracil/leucovorin (5‐FU/LV) maintenance was 21 (interquartile range: 11–41) weeks; that of 5‐FU/LV ± bevacizumab maintenance was 16 (6–31) weeks. Median OS from randomisation was 40.2 (95% confidence interval: 30.3–50.4) and 39.1 (34.2–63.0) months for panitumumab plus 5‐FU/LV maintenance and 24.1 (17.7–33.0) and 28.9 (21.0–32.0) months for 5‐FU/LV ± bevacizumab maintenance in PRIME and PEAK, respectively. Median PFS from randomisation was 16.6 (11.3–23.6) and 15.4 (11.6–18.4) months for panitumumab plus 5‐FU/LV maintenance and 12.6 (9.4–16.2) and 13.1 (9.5–16.6) months for 5‐FU/LV ± bevacizumab maintenance in PRIME and PEAK, respectively. From oxaliplatin discontinuation, median OS was 33.9 (24.7–42.8) and 33.5 (24.5–54.9) months for panitumumab plus 5‐FU/LV maintenance and 16.4 (12.4–24.1) and 23.3 (15.7–26.3) months for 5‐FU/LV ± bevacizumab maintenance in PRIME and PEAK, respectively; PFS was 11.7 (7.8–19.2) and 9.7 (5.8–14.8) months and 7.1 (5.6–10.2) and 7.0 (3.9–10.6) months, respectively. The most frequently reported adverse events were rash, fatigue and diarrhoea. Maintenance of panitumumab plus 5‐FU/LV after oxaliplatin discontinuation was well tolerated and may be an acceptable treatment paradigm for patients demonstrating a good response to first‐line treatment. Prospective studies are warranted., What's new? Panitumumab is an anti‐EGFR antibody used in the treatment of RAS wild‐type metastatic colorectal cancer. But is it useful for long‐term therapy in these patients, especially after more toxic therapies like oxaliplatin are discontinued? In this retrospective analysis, the authors found that a maintenance regimen including panitumumab was well tolerated and may be associated with better outcomes than non‐panitumumab strategies. Patients who received panitumumab‐based maintenance therapy were also more likely to have had a good response to first‐line treatment. The results from this study indicate that further, prospective studies are warranted.

Introduction\ud \ud The efficacy of adding denosumab to standard first-line chemotherapy for advanced NSCLC patients has been evaluated in two separate randomised trials (SPLENDOUR and AMGEN-249). In this pooled analysis, we will assess the combination-treatment effect in the largest available population, in order to conclude about the potential impact of denosumab in NSCLC.\ud \ud \ud \ud Methods\ud \ud Both trials included in this combined analysis, were randomised (SPLENDOUR 1:1, AMGEN-249 2:1) multi-centre trials stratified by histology, bone metastasis, geographical region and for SPLENDOUR only, ECOG PS. Cox proportional hazards models, were used to assess the treatment effect with respect to overall survival (OS; primary endpoint) and progression-free survival (PFS; secondary endpoint). Heterogeneity between trials was assessed, and subgroup analyses were performed.\ud \ud \ud \ud Results\ud \ud The pooled analysis was based on 740 randomised patients (SPLENDOUR:514; AMGEN-249:226), with 407 patients in the chemotherapy-denosumab arm and 333 in the chemotherapy-alone arm.\ud \ud \ud \ud In the chemotherapy-denosumab arm, at a median follow-up of 22.0 months, 277 (68.1%) deaths were reported with median OS 9.2 months (95%CI:[8.0–10.7]), while in the chemotherapy-alone arm, with similar median follow-up of 20.3 months, 230 (69.1%) deaths with median OS 9.9 months (95%CI:[8.2–11.2]). No significant denosumab effect was found (HR = 0.98; 95%CI:[0.82–1.18]; P = 0.85).\ud \ud \ud \ud Among subgroups, interaction was found between treatment and histology subtypes (P = 0.020), with a statistically significant benefit in the squamous group (HR = 0.70; 95%CI:[0.49–0.98]; P = 0.038), from 7.6 to 9.0 months median OS.\ud \ud \ud \ud With respect to PFS, 363 (89.2%) and 298 (89.5%) events were reported in the chemotherapy-denosumab and chemotherapy-alone arms, respectively, with corresponding medians 4.8 months (95%CI:[4.4–5.3]) and 4.9 months (95%CI:[4.3–5.4]). HR for PFS was 0.97 (95%CI:[0.83–1.15]; P = 0.76), indicating that no significant denosumab benefit existed for PFS.\ud \ud \ud \ud Conclusion\ud \ud In this pooled analysis, no statistically significant improvement was shown in PFS/OS with the combination of denosumab and chemotherapy for advanced NSCLC and no meaningful benefit in any of the subgroups.

Background Medication-related osteonecrosis of the jaw (MRONJ) is an infrequent, but potentially serious, adverse event that can occur after exposure to bone-modifying agents (BMAs; e.g., bisphosphonates, denosumab, and antiangiogenic therapies). BMAs are typically used at higher doses to prevent skeletal-related events in cancer patients and at lower doses for osteoporosis/bone loss. MRONJ can cause significant pain, reduce quality of life, and can be difficult to treat, requiring a multiprofessional approach to care. Methods We reviewed the literature and guidelines to summarize a practical guide on MRONJ for nurses and other allied healthcare professionals. Results While there is a risk of MRONJ with BMAs, this should be considered in relation to the benefits of treatment. Nurses and other allied healthcare professionals can play a key role alongside physicians and dentists in assessing MRONJ risk, identifying MRONJ, counseling the patient on the benefit–risk of BMA treatment, preventing MRONJ, and managing the care pathway of these patients. Assessing patients for MRONJ risk factors before starting BMA treatment can guide preventative measures to reduce the risk of MRONJ. Nurses can play a pivotal role in facilitating multiprofessional management of MRONJ by communicating with patients to ensure compliance with preventative measures, and with patients’ physicians and dentists to ensure early detection and referral for prompt treatment of MRONJ. Conclusions This review summarizes current evidence on MRONJ and provides practical guidance for nurses, from before BMA treatment is started through to approaches that can be taken to prevent and manage MRONJ in patients receiving BMAs.

Aim: Correct identification of RAS gene variants is key for targeted treatment decisions in patients with metastatic colorectal cancer. Published RAS mutation rates differ and could be influenced by several factors including testing methods. This study aimed to describe the performance of laboratories to correctly identify RAS variants over time and to understand how RAS testing has evolved in Europe. Materials & methods: Misclassification and test failure rates were calculated and related to the used test methodology for 239 unique laboratories participating in external quality assessment for metastatic colorectal cancer between 2013 and 2018. In addition, 33 laboratories completed a survey aiming to obtain more details on their routine testing strategies, number of samples analyzed and RAS mutation rates between 2013 and 2017. Results: The mutation status was correctly analyzed in 96.1% (N = 5471) RAS and BRAF tests. A total of 4.6% (N = 2860) RAS tests included false-negative results. In 1.6% (N = 5562) RAS and BRAF tests, an analysis failure occurred. Misclassifications and technical failures both decreased between 2013 and 2018. The number of next-generation sequencing users increased from 6.9% (N = 130) in 2013 to 44.6% (N = 112) in 2018. Over time, more codons were included in the methodologies, yet 23.2% (N = 112) did not offer full RAS testing (exon 2, 3, 4) in 2018. Based on the survey the overall RAS mutation rate was estimated as 45.2% (N = 27,325). Conclusion: This is the largest observational study reporting RAS mutation rates to-date. There was no trend of RAS mutation rates over time despite having a clear shift to more sensitive tests and increased quality of testing. ispartof: Colorectal Cancer vol:9 issue:1 status: Published online

Background In Europe, treatment of metastatic colorectal cancer (mCRC) with panitumumab requires prior confirmation of RAS wild-type mutation status. Two studies – a physician survey and a medical records review (MRR) – were conducted to evaluate the use of panitumumab and awareness among prescribing oncologists of the associated RAS testing requirements in clinical practice. Methods Both studies enrolled participants from nine European countries and were carried out in three consecutive rounds. Rounds 1 and 2 (2012–2013) examined KRAS (exon 2) testing only; the results have been published in full previously. Round 3 (2014–2015) examined full RAS testing (exons 2, 3, 4 of KRAS and NRAS) and was initiated following a change in prescribing guidelines, from requiring KRAS alone to requiring full RAS testing. For the physician survey, telephone interviews were conducted with oncologists who had prescribed panitumumab to patients with mCRC in the previous 6 months. For the MRR, oncologists were asked to provide anonymised clinical information, extracted from their patients’ records. Results In Round 3, 152 oncologists and 131 patients’ records were included in the physician survey and MRR, respectively. In Round 3 of the physician survey, 95.4% (n = 145) of participants correctly identified that panitumumab should only be prescribed in RAS wild-type mCRC compared with 99.0% (n = 298) of 301 participants in Rounds 1 and 2, responding to the same question about KRAS testing. In Round 3 of the MRR, 100% (n = 131) of patients included in the study had confirmed KRAS or RAS wild-type status prior to initiation of panitumumab compared with 97.7% (n = 299) of 306 patients in Rounds 1 and 2 (KRAS only). Of those patients in Round 3, 83.2% (n = 109) had been tested for RAS status and 16.8% (n = 22) had been tested for KRAS status only. Conclusions Physicians’ adherence to prescribing guidelines has remained high over time in Europe, despite the change in indication for panitumumab treatment, from KRAS to RAS wild-type mCRC. Additionally, this study demonstrates the uptake of full RAS testing among the majority of oncologists and pathologists. Electronic supplementary material The online version of this article (10.1186/s12885-017-3740-4) contains supplementary material, which is available to authorized users.

Purpose To report exploratory analyses of early tumour shrinkage (ETS) and depth of response (DpR) in patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC), receiving the first-line treatment in three randomised panitumumab trials. Methods Data from the PRIME (NCT00364013), PEAK (NCT00819780) and PLANET (NCT00885885) studies were included. Median DpR, the proportion of patients achieving ETS ≥ 20% or ≥ 30% at week 8, and the impact of ETS and DpR (including by category) on outcome were analysed. Factors associated with ETS and DpR and the optimal ETS/DpR cut-off values for predicting improved overall survival (OS) were assessed. Results Overall, 505, 170 and 53 patients had RAS WT mCRC in PRIME, PEAK and PLANET, respectively. Patients receiving panitumumab had higher ETS rates (≥ 30%: PRIME 59% vs. 38%; PEAK 64% vs. 45%) and greater DpR (PRIME: 54% vs. 46%; PEAK: 65% vs. 46%) than those receiving treatment without panitumumab. In multiple regression analyses, panitumumab treatment, liver-only metastases and WT BRAF status were consistently associated with improved ETS and DpR outcomes. Irrespective of treatment, ETS and DpR were associated with improved progression-free survival, overall survival and resection rates; most resections occurred in patients in the two highest DpR categories. In PRIME and PEAK, respectively, the optimal cut-offs for predicting improved OS were 32 and 34% for ETS, and 59 and 70% for DpR. Conclusions These exploratory analyses suggest that panitumumab is associated ETS and DpR benefits in patients with RAS WT mCRC and that achieving these endpoints during first-line treatment is linked with favourable outcomes. Electronic supplementary material The online version of this article (doi:10.1007/s00432-017-2534-z) contains supplementary material, which is available to authorized users.

A systematic literature review was conducted to quantify populations of patients with primary breast cancer in whom bone metastases were detected at study start or during follow-up. Searches were performed in PubMed and EMBASE using terms related to breast cancer and bone metastases. Articles had to have been published 01/01/99–31/12/13, and to report data on the proportion of patients with bone metastases among patients with breast cancer. In total, 156 articles were included in the meta-analysis. A median of 12% of patients with stage I–III breast cancer developed bone metastases during a median follow-up of 60 months. Of patients who developed metastatic disease during follow-up, 55% (median) had bone metastases. Of those with metastatic breast cancer at study start, 58% (median) had bone metastases. These data help to inform on the global burden of bone metastases by defining patient populations that are at risk of developing bone metastases., SCOPUS: re.j, info:eu-repo/semantics/published

Purpose To report planned final overall (OS) and progression-free survival (PFS) analyses from the phase II PEAK trial (NCT00819780). Methods Patients with previously untreated, KRAS exon 2 wild-type (WT) metastatic colorectal cancer (mCRC) were randomised to mFOLFOX6 plus panitumumab or bevacizumab. The primary endpoint was PFS; secondary endpoints included OS, objective response rate, duration of response (DoR), time to response, resection and safety. Treatment effect by tumour RAS status was a prespecified objective. Exploratory analyses included early tumour shrinkage (ETS) and depth of response (DpR). Results One hundred seventy patients had RAS WT and 156 had RAS WT/BRAF WT mCRC. Median PFS was longer for panitumumab versus bevacizumab in the RAS WT (12.8 vs 10.1 months; hazard ratio (HR) = 0.68 [95% confidence intervals (CI) = 0.48–0.96]; p = 0.029) and RAS WT/BRAF WT (13.1 vs 10.1 months; HR = 0.61 [95% CI = 0.42–0.88]; p = 0.0075) populations. Median OS (68% OS events) for panitumumab versus bevacizumab was 36.9 versus 28.9 months (HR = 0.76 [95% CI = 0.53–1.11]; p = 0.15) and 41.3 versus 28.9 months (HR = 0.70 [95% CI = 0.48–1.04]; p = 0.08), in the RAS WT and RAS WT/BRAF WT populations, respectively. Median DoR (11.4 vs 9.0 months; HR = 0.59 [95% CI = 0.39–0.88]; p = 0.011) and DpR (65.0 vs 46.3%; p = 0.0018) were improved in the panitumumab group. More panitumumab patients experienced ≥30% ETS at week 8 (64 vs 45%; p = 0.052); ETS was associated with improved PFS/OS. No new safety signals occurred. Conclusions First-line panitumumab + mFOLFOX6 increases PFS versus bevacizumab + mFOLFOX6 in patients with RAS WT mCRC. Electronic supplementary material The online version of this article (doi:10.1007/s00384-017-2800-1) contains supplementary material, which is available to authorized users.

Laboratories require customized feedback on improving biomarker testing practices. A workshop was organized for laboratories that participated in a European external quality assessment scheme to resolve issues related to the estimation of neoplastic cell percentage and tissue quality for RAS testing for colorectal cancer. An interactive course about tissue quality took place to stress the importance of the pre-analytical phase. During a microscopic session, five H&E stained tumor tissue slides were discussed and neoplastic cell percentages estimated. Participants included 4 pathologists, 3 molecular biologists, a technologist and a clinical geneticist from 7 laboratories. In six laboratories, tumor contents are checked routinely by visual estimation by the pathologist. The average difference between the lowest and highest estimation was 22%. During the workshop the importance of the pre-analytical phase was stressed and feedback was provided. Such initiatives can contribute in improving biomarker testing standards in Europe ispartof: Biomarkers Journal vol:5 issue:1 pages:1-1 status: Published online

Introduction This study aimed to provide a description of existing measures for the prevention and management of epidermal growth factor receptor inhibitor monoclonal antibody-induced skin toxicities and factors impacting patients’ adherence to those measures in France, Germany, and Spain. Materials and Methods The study consisted of 2 separate surveys. Health care professionals (HCPs; oncologists and nurses) in France, Germany, and Spain were interviewed, and patients with metastatic colorectal cancer and head-and-neck cancer in France and Germany self-completed questionnaires. The study was conducted between February and July 2018. Results A total of 53 oncologists, 44 nurses, and 143 patients participated in the study. HCPs stated that skin toxicities moderately (52%) or severely (28%) impacted patient care. Ninety percent of HCPs reported routine provision of prophylactic measures. The great majority of patients self-reported adherence with the prophylactic (80% to 88% depending on the type of measures) and reactive (93% to drug prescription) skin toxicity recommendations. HCPs estimated patient adherence to be 45% for full adherence and 40% for partial adherence. Most HCPs reported a positive or very positive impact of preventive measures and recommendations on skin toxicity incidence and severity, patients' quality of life, and various aspects of quality of anti-cancer treatment. Conclusions Skin toxicities are an important adversity negatively impacting on patient care. However, despite the positive perception of the effectiveness of skin toxicity prophylaxis, almost one-third of oncology centers did not provide formal guidelines, and 10% of HCPs did not provide routine prophylactic measures. Patient adherence appears to be high for epidermal growth factor receptor inhibitor monoclonal antibody-induced skin toxicity prevention measures.

Context Recent developments in the treatment of metastatic castration-resistant prostate cancer (mCRPC) have led to uncertainty about the optimal sequence of agents. Objective To review and assess treatment options and sequence in patients with mCRPC. Evidence acquisition To identify data on the optimal use of approved treatments, we searched PubMed for studies on the use of recently approved agents for men with mCRPC published before March 2015. Phase 3 and other key studies were included in the review of efficacy and safety. In this review, we offer our critical interpretation of potential treatment sequences for drug use in the light of our clinical experience. Evidence synthesis Since 2004, the treatment landscape for mCRPC has changed dramatically following the approval of docetaxel, abiraterone acetate, enzalutamide, cabazitaxel, denosumab, and radium-223 chloride. To date, only small-scale studies have been undertaken that provide evidence on the sequencing of these treatments. Ideally, randomised, prospective studies would evaluate different sequence options thoroughly so that physicians could make evidence-based decisions, but the number of new agents makes this impractical. When deciding which treatment to prescribe, physicians will need to use the available evidence combined with their own clinical judgement. The potential for cross-resistance between taxanes and hormonal therapies and the possibility that patients might not be suitable for aggressive therapies in later lines should be taken into account. Prevention of complications associated with bone metastases should also be a key consideration because of the major impact these events have on quality of life and healthcare costs. Conclusions The recent approval of numerous new agents has resulted in considerable improvements in outcomes for patients with mCRPC. Further studies determining the optimal treatment algorithm, in addition to open discussion of best practice among physicians, are required to ensure patients obtain the maximum possible benefit from their treatment. Patient summary In recent years a large number of new treatment options have been approved for use in men with prostate cancer. In the absence of clinical trials assessing the use of one option versus another in specific patient groups, it is important to review the currently published evidence to try to understand patients receive the best treatment options in the correct order.

Background: To investigate tumour biomarker status and efficacy of first-line panitumumab+FOLFIRI for metastatic colorectal carcinoma (mCRC). Methods: 154 patients received first-line panitumumab + FOLFIRI every 14 days. Primary end point was objective response rate (ORR). Data were analysed by tumour RAS (KRAS/NRAS) and BRAF status, and baseline amphiregulin (AREG) expression. Results: Objective responses occurred more frequently in RAS wild type (WT) (59%) vs RAS mutant (MT) (41%) mCRC and in RAS WT/BRAF WT (68%) vs RAS or BRAF MT (37%) disease. Median response duration was longer in RAS WT (13.0 months) vs RAS MT (5.8 months) (hazard ratio (HR): 0.16). Median progression-free survival was longer in RAS WT vs MT (11.2 vs 7.3 months; HR, 0.37) and was also longer in RAS WT/BRAF WT vs RAS or BRAF MT (13.2 vs 6.9 months; HR, 0.25). Incidence of adverse events was similar regardless of RAS/BRAF status, and no new safety signals were noted. Among patients with RAS WT tumours, ORR was 67% with high AREG expression and 38% with low AREG expression. Conclusions: First-line panitumumab+FOLFIRI was associated with favourable efficacy in patients with RAS WT and RAS WT/BRAF WT vs MT mCRC tumours and was well tolerated.

Biomarker analysis for colorectal cancer has been shown to be reliable in Europe with 97% of samples tested by EQA participants to be correctly classified. This study focuses on errors during the annual EQA assessment. The aim was to explore the causes and actions related to the observed errors and to provide feedback and assess any improvement between 2016 and 2017. An electronic survey was sent to all laboratories with minimum one genotyping error or technical failure on ten tumor samples. A workshop was organized based on 2016 survey responses. Improvement of performance in 2017 was assessed for returning participants (n = 76), survey respondents (n = 13) and workshop participants (n = 4). Survey respondents and workshop participants improved in terms of (maximum) analysis score, successful participation, and genotyping errors compared to all returning participants. In 2016, mostly pre- and post-analytical errors (both 25%) were observed caused by unsuitability of the tumor tissue for molecular analysis. In 2017, most errors were due to analytical problems (50.0%) caused by methodological problems. The most common actions taken (n = 58) were protocol revisions (34.5%) and staff training (15.5%). In 24.1% of issues identified no action was performed. Corrective actions were linked to an improved performance, especially if performed by the pathologist. Although biomarker testing has improved over time, error occurrence at different phases stresses the need for quality improvement throughout the test process. Participation to quality improvement projects and a close collaboration with the pathologist can have a positive influence on performance. Electronic supplementary material The online version of this article (10.1007/s00428-019-02525-9) contains supplementary material, which is available to authorized users.

Purpose: Mutations in EGFR pathway genes are poor prognostic indicators in patients with metastatic colorectal cancer. Plasma analysis of cell-free DNA is a minimally invasive and highly sensitive method to detect somatic mutations in tumors. Experimental Design: Plasma samples collected from panitumumab-treated patients in the ASPECCT study at baseline and safety follow-up (SFU) were analyzed by a next-generation sequencing–based approach for extended RAS mutant allele frequency as a continuous variable and their association with clinical outcomes and the mutational prevalence of 63 cancer-related genes. The correlation between patient outcome and baseline mutational status of EGFR pathway genes was also examined. Results: Overall, 261 patients in the panitumumab arm had evaluable plasma samples. Patients with a higher RAS mutant allele frequency at baseline had worse clinical outcomes than those with a lower frequency (P < 0.001, Cox PH model); however, RAS mutations did not necessarily preclude patients from deriving benefits. The objective response rate (complete or partial response) was 10.8% for patients with baseline RAS mutations and 21.7% for those with BRAF mutations. The 63-gene panel analysis revealed an increase in tumor mutational burden from baseline to SFU (P < 0.001, Wilcoxon signed rank test). Baseline mutations in EGFR pathway genes, when analyzed both categorically and continuously, were associated with shorter survival. Conclusions: When mutations in EGFR pathway genes were analyzed continuously, higher mutant allele frequency correlated with poorer outcomes. However, extended RAS mutation, by itself, did not preclude clinical responses to panitumumab in a monotherapy setting.

The authors would like to include the following changes in the published article.

There is a need to identify patients who may benefit from particular treatments. We investigated prognosis in 915 patients with mCRC from 2 phase III trials of panitumumab plus chemotherapy, based on Kohne category and BRAF status. Both Kohne category and BRAF status predicted outcomes in terms of PFS and OS, and panitumumab provided benefits over chemotherapy alone. Background: Kohne prognostic score is used to classify patients with metastatic colorectal cancer (mCRC) as high, intermediate, or low risk. Using data from 2 phase III trials, we analyzed survival in patients categorized according to Kohne prognostic category and virus-induced rapidly accelerated fibrosarcoma murine sarcoma viral oncogene homolog B (BRAF) mutation. Patients and Methods: PRIME (Panitumumab Randomized Trial In Combination With Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy) (first-line) and 20050181 (second-line) were studies of chemotherapy with or without panitumumab. Progression-free survival (PFS) and overall survival (OS) were analyzed retrospectively in rat sarcoma viral oncogene homolog (RAS) wild type (WT) and RAS WT+BRAF WT mCRC in each Kohne category, and in BRAF mutant (MT) mCRC. Results: In PRIME (n = 495) and 20050181 (n = 420), 53 (11%) and 44 (10%) patients, respectively, had BRAF MT mCRC. Of the RAS WT+BRAF WT/unknown populations, 85/267/90 and 82/211/83 were categorized as high/medium/low risk, respectively. PFS and OS hazard ratios (HRs), adjusted for Kohne group, for patients with RAS WT + BRAF WT/unknown mCRC favored panitumumab with chemotherapy versus chemotherapy alone in both studies. In PRIME, the PFS HR was 0.74 (95% confidence interval [CI], 0.61-0.90) and OS HR was 0.78 (95% CI, 0.64-0.95). In 20050181, PFS and OS HRs were 0.80 (95% CI, 0.65-0.99) and 0.78 (95% CI, 0.62-0.99), respectively. Median PFS and OS were lower in patients with BRAF MT mCRC than in any of the 3 risk categories for patients with RAS WT+BRAF WT/unknown mCRC. Conclusion: During first- and second-line treatment, Kohne prognostic score allows accurate risk classification in RAS WT mCRC. BRAF MT mCRC should be classified as high risk regardless of other parameters. Panitumumab with chemotherapy might provide survival benefits versus chemotherapy alone in RAS WT and RAS WT+BRAF WT/unknown mCRC, overall and across risk categories. (C) 2017 The Authors. Published by Elsevier Inc.

Background Despite existing clinical guidelines on bone health in patients with cancer (ESMO 2014), the use of recommended BTA is sub-optimal for many patients. It is unclear if physicians’ decisions are aligned with ESMO’s guidelines to initiate BTA as soon as bone metastasis (BM) are diagnosed, irrespective of symptomatic disease, in breast cancer (BC) or castration-resistant prostate cancer (CRPC) patients. The current study describes BTA initiation in BC or CRPC patients with BM treated within routine clinical settings. Methods Data reported by physicians (oncologists or urologists) in Europe via online data capture using physician-directed surveys and patients’ medical records as required were analysed. Adult BC or physician-defined CRPC patients included in the study received active anti-cancer treatment between February 2015 and April 2015. Adherence to the ESMO 2014 guidelines was defined as the proportion of patients with a BTA initiation within 3 months ( Results A total of 731 physicians reported data on 1,857 patients treated for their cancer in Europe. For BC patients (n = 1,195) and CRPC patients (n = 662) treated by oncologists, only 84% and 61%, respectively, received their first BTA within 3 months of BM diagnosis. Adherence to the ESMO 2014 guidelines was lower (55%) in the 118 urologist-treated CRPC patients. Most physicians (87%) across all specialties considered the presence or absence of bone pain as the most important factor when assessing the risk of bone complications. Bone pain was also reported by the physicians as a main reason for BTA initiation in nearly three-quarters of BTA-treated patients (71% BC, 75% CRPC). Overall, 56% of physicians considered bone pain to be either a bone complication (58% oncologists vs 48% urologists) or a skeletal-related event (53% oncologists vs 68% urologists). Conclusions Adherence to ESMO’s guidelines on bone health differed by tumour type and by physician specialty within solid tumour patients treated in routine clinical settings. Despite ESMO’s guidance on bone protection irrespective of symptomatic disease, bone pain appeared to be a trigger for BTA initiation in routine clinical practice. Clinical trial identification Amgen study 20150107. Legal entity responsible for the study Amgen (Europe) GmbH. Funding Amgen (Europe) GmbH. Disclosure A. Rider: Full / Part-time employment: Adelphi Group Ltd. A.M. Seesaghur: Shareholder / Stockholder / Stock options, Full / Part-time employment: Amgen; Shareholder / Stockholder / Stock options, Full / Part-time employment: Amgen. K. Lewis: Full / Part-time employment: Adelphi Group Ltd. D. Bluff: Full / Part-time employment: Adelphi Group Ltd. A. Marongiu: Full / Part-time employment, Andrea Marongiu is a contract worker at Amgen. G. Demonty: Shareholder / Stockholder / Stock options, Full / Part-time employment: Amgen.

Background The aim of this study was to evaluate the optimal sequence of targeted therapies (epidermal growth factor receptor inhibitors (EGFRi) and vascular endothelial growth factor inhibitors (VEGFi)), combined with chemotherapy, in patients with RAS wild-type (WT) metastatic colorectal carcinoma (mCRC). Exploratory analyses of overall survival (OS) for patients treated with either first-line panitumumab (EGFRi) and second-line VEGFi therapy, or first-line bevacizumab (VEGFi) and second-line EGFRi, were conducted. Methods Patients from PEAK (NCT00819780), PRIME (NCT00364013) and Study 181 (NCT00339183), with RAS WT or RAS WT/BRAF WT tumours, were included in the analyses. OS data were pooled for patients receiving first-line panitumumab (PEAK and PRIME) or first-line bevacizumab (PEAK and 181), followed by second-line VEGFi or EGFRi, respectively. Results Overall, 104 RAS WT patients were included (n=66 panitumumab→VEGFi, n=38 bevacizumab→EGFRi). At the time of final data analysis, 63.6% versus 92.1% of patients in the panitumumab→VEGFi versus bevacizumab→EGFRi arms had died; median OS was 36.8 versus 27.8 months, respectively (HR 0.65; 95% CI 0.42 to 1.03). The OS HR for patients with RAS WT/BRAF WT mCRC overall was 0.58 (95% CI 0.36 to 0.95) and was 0.56 (95% CI 0.30 to 1.04) in those with left-sided tumours. Conclusion Although numbers are small, these exploratory analyses suggest a trend towards improved OS for first-line panitumumab plus chemotherapy followed by second-line VEGFi, compared with first-line bevacizumab followed by second-line EGFRi in patients with RAS WT and RAS WT/BRAF WT mCRC. Large prospective randomised trials are needed to further evaluate the optimum sequence of EGFRi/VEGFi in mCRC.

The epidermal growth factor receptor (EGFR) is involved in development and progression of some gastrointestinal cancers, and is targeted by monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs) used to treat these conditions. Targeted agents are generally better tolerated than conventional chemotherapy, but have characteristic toxicities that can affect adherence, dosing, and outcomes. Skin conditions are the most common toxicities associated with EGFR inhibitors, particularly papulopustular rash. Other common toxicities include mucosal toxicity, electrolyte imbalances (notably hypomagnesaemia), and diarrhoea, while the chimaeric mAb cetuximab is also associated with increased risk of infusion reactions. With appropriate prophylaxis, the incidence and severity of these events can be reduced, while management strategies tailored to the patient and the degree of toxicity can help to ensure continuation of anti-cancer therapy. Here, we review the main toxicities associated with EGFR-inhibiting mAbs and TKIs in patients with gastrointestinal cancers, and provide recommendations for prophylaxis and treatment.

Background The aim of this study was to evaluate the optimal sequence of targeted therapies (epidermal growth factor receptor inhibitors (EGFRi) and vascular endothelial growth factor inhibitors (VEGFi)), combined with chemotherapy, in patients with RAS wild-type (WT) metastatic colorectal carcinoma (mCRC). Exploratory analyses of overall survival (OS) for patients treated with either first-line panitumumab (EGFRi) and second-line VEGFi therapy, or first-line bevacizumab (VEGFi) and second-line EGFRi, were conducted. Methods Patients from PEAK (NCT00819780), PRIME (NCT00364013) and Study 181 (NCT00339183), with RAS WT or RAS WT/ BRAF WT tumours, were included in the analyses. OS data were pooled for patients receiving first-line panitumumab (PEAK and PRIME) or first-line bevacizumab (PEAK and 181), followed by second-line VEGFi or EGFRi, respectively. Results Overall, 104 RAS WT patients were included (n=66 panitumumab→VEGFi, n=38 bevacizumab→EGFRi). At the time of final data analysis, 63.6% versus 92.1% of patients in the panitumumab→VEGFi versus bevacizumab→EGFRi arms had died; median OS was 36.8 versus 27.8 months, respectively (HR 0.65; 95% CI 0.42 to 1.03). The OS HR for patients with RAS WT/ BRAF WT mCRC overall was 0.58 (95% CI 0.36 to 0.95) and was 0.56 (95% CI 0.30 to 1.04) in those with left-sided tumours. Conclusion Although numbers are small, these exploratory analyses suggest a trend towards improved OS for first-line panitumumab plus chemotherapy followed by second-line VEGFi, compared with first-line bevacizumab followed by second-line EGFRi in patients with RAS WT and RAS WT/ BRAF WT mCRC. Large prospective randomised trials are needed to further evaluate the optimum sequence of EGFRi/VEGFi in mCRC.

The aim of this review is to examine the evidence available supporting the use of the docetaxel plus trastuzumab combination for patients with HER-2-positive metastatic breast cancer. The results of trials involving this combination are summarized, with an emphasis on efficacy and cardiotoxicity data. Finally, this article attempts to identify areas of uncertainty where new trials are warranted to improve our knowledge regarding optimal care for patients with HER-2-positive metastatic breast cancer.

530 Background: Patients with metastatic colorectal cancer (mCRC) must have a confirmed RAS wild-type status before starting panitumumab (pmab). Two studies, a physician survey and a medical records review (MRR), were carried out to evaluate physician awareness of the need for biomarker testing in mCRC. Methods: Both studies were carried out in three rounds. Rounds 1 and 2 (2012–14) examined KRAS testing only as they were completed before guidelines changed, and have been published previously. Round 3 (2014–15), reported here, was performed after guidelines changed and covered full RAS testing. Participants were from nine European countries:France, Germany, Italy, Spain, the Czech Republic, the Netherlands, Belgium, Denmark, and Sweden. For the survey, oncologists who had prescribed pmab to mCRC patients in the previous 6 months were interviewed by telephone using a standard questionnaire.For the MRR,oncologists were asked to provide clinical information extracted from their patients’ medical records. Results: 152 oncologists and 131 patients’ records were included in Round 3 of the physician survey and the MMR, respectively, compared with 301 oncologists and 306 records in Rounds 1 and 2. In Round 3 of the physician survey, 95.4% (n = 145) of participants correctly reported that pmab should be prescribed in RAS wild-type mCRC only, compared with 99.0% (n = 298) in Rounds 1 and 2, responding to the same question about KRAS testing. In Round 3 of the MRR, 100% (n = 131) of patients had a confirmed RAS or KRAS wild-type status prior to initiation of pmab. Of those patients, 83.2% (n = 109) were tested for RAS status and 16.8% (n = 22) were tested for KRAS status only. Conclusions: Round 3 of the survey demonstrated a high level of knowledge amongst oncologists about the need for RAS testing in mCRC. The MRR supported these findings, showing that this knowledge is being applied to clinical practice. Comparisons between Round 3 and Rounds 1 and 2 show that physician awareness and adherence to prescribing guidelines remained high over time, despite recommendations changing with RAS testing replacing KRAS testing.

Purpose The After Mapping of the Axilla: Radiotherapy or Surgery? (AMAROS) phase III study compares axillary lymph node dissection (ALND) and axillary radiation therapy (ART) in early breast cancer patients with tumor-positive sentinel nodes. In the ART arm, the extent of nodal involvement remains unknown, which could have implications on the administration of adjuvant therapy. In this preliminary analysis, we studied the influence of random assignment to ALND or ART on the choice for adjuvant treatment. Patients and Methods In the first 2,000 patients enrolled in the AMAROS trial, we analyzed the administration of adjuvant systemic therapy. Multivariate analysis was used to assess variables affecting the administration of adjuvant chemotherapy. Adjuvant therapy was applied according to institutional guidelines. Results Of 2,000 patients, 566 patients had a positive sentinel node and were treated per random assignment. There was no significant difference in the administration of adjuvant systemic therapy. In the ALND and ART arms, 58% (175 of 300) and 61% (162 of 266) of the patients, respectively, received chemotherapy. Endocrine therapy was administered in 78% (235 of 300) of the patients in the ALND arm and in 76% (203 of 266) of the patients in the ART arm. Treatment arm was not a significant factor in the decision, and no interactions between treatment arm and other factors were observed. Multivariate analysis showed that age, tumor grade, multifocality, and size of the sentinel node metastasis significantly affected the administration of chemotherapy. Within the ALND arm, the extent of nodal involvement remained not significant in a sensitivity multivariate analysis. Conclusion Absence of knowledge regarding the extent of nodal involvement in the ART arm appears to have no major impact on the administration of adjuvant therapy.

At present, the biology of breast cancer remains poorly understood. Currently, lymph node metastases, tumor grade, and size, and expression of hormone receptors provide the only true prognostic and predictive factors related to clinical outcome and response to treatment, respectively. Many other potential candidates have been suggested but, due to their limited predictive power, have not been widely accepted by the general oncological community. These histopathological features do not allow us any insight into breast cancer biology, however, and these prognostic classifications are far from perfect. At present, due to these limitations many clinicians consider prescribing adjuvant treatment to many women with early breast cancer to reduce the risk of relapse, only to benefit a few, thus exposing many patients to unnecessary toxicity. Since the publication of the complete sequence of the human genome however, a new era of research has begun [1]. More than 3 billions base pairs form the 30,000-40,000 genes that code all the required genetic information of a particular individual. The functions of the vast majority of these genes are still unknown. A combination of circumstances, including the advent of array-based technology and progress in the human genome initiative, have provided the ideal opportunity to begin efforts aimed at performing comprehensive molecular and genetic profiling of human cancers. The ability to interrogate tens of thousands of genes simultaneously by using microarray technologies has significantly changed our approach to the analysis of expression profiles, and has also led to an increased understanding of the basic biology of breast cancer. Such comprehensive technologies permit the assessment not only of individual genes, but also of clusters of genes that are coordinately expressed to generate "fingerprints" of biological states of the cells of origin. This is especially important given that it has become increasingly evident that the biology of cancer, particularly solid tumors, is determined by the behavior of many genes, rather than a few. Although there are other techniques that analyze differences in gene expression, none matches the ease and the comprehensive nature of the interrogation associated with c-DNA- or oligonucleotide-based microarray analysis. A list of the terms commonly used in this field is given in Table 30.1. (Table presented). © Springer-Verlag Berlin Heidelberg 2006.

The aim of this review article is to examine the available evidence regarding diagnosis and treatment of HER-2 positive breast cancer. This group of breast tumours (up to 30% of the total number of breast cancers) is known for having a more aggressive behaviour. The current recommendations for HER-2 positive tumour diagnosis are discussed since accurate identification of HER-2 amplification or overexpression is key for allowing a correct risk assessment and treatment. HER-2 positive tumours can be treated with trastuzumab (Herceptin, Hoffmann-La Roche, Basel, Switzerland), a monoclonal antibody targeted against the HER-2 receptor. The role of this drug in the metastatic, adjuvant and neoadjuvant setting is reviewed. The results of the recently reported adjuvant trials are commented, as the positive results of these trials changed the standard of care for patients with this particular type of breast cancer.

The 2003 St. Gallen consensus panel divided the many available adjuvant chemotherapy (CT) regimens into those with "standard efficacy" (ACx4, CMFx6) and those with "superior efficacy" (FA(E)Cx6, CA(E)Fx6, A(E)-->CMF, TACx6, ACx4--> paclitaxel (P)x4 or docetaxel (D)x4) but also greater complexity, toxicity and cost. This paper will summarize the latest information on long-term side effects of the "superior" regimens and 5-year benefits reported in taxane trials, including those of a "new" sequential regimen, FECx3--> docetaxelx3. Rapidly expanding evidence of marked heterogeneity in the magnitude of CT benefits according to the tumour oestrogen receptor (ER) status, a claim made for many years by IBCSG investigators, will be reviewed; it will lead to the conclusion that a revolution needs to take place in the way oncologists think about the CT added value and design adjuvant clinical trials. The conclusions proposed to the 2005 St. Gallen consensus panel are that: adequately dosed anthracycline-based CT regimens remain an acceptable standard for many women; a lower threshold for using taxanes in sequence or combination with anthracyclines (A) is justified in the presence of an ER-negative or low-ER tumour status, other aggressive biologic features (such as HER-2 overexpression), fear about A-induced cardiotoxicity; no recommendation can yet be made as far as the optimal taxane-A regimen, the best taxane or the best taxane schedule.