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Background: Genomic tumour profiling has a crucial role in the management of patients with solid cancers, as it helps selecting and prioritising therapeutic interventions based on prognostic and predictive biomarkers, as well as identifying markers of hereditary cancers. Harmonised approaches to interpret the results of genomic testing are needed to support physicians in their decision making, prevent inequalities in precision medicine and maximise patient benefit from available cancer management options., Methods: The European Society for Medical Oncology (ESMO) Translational Research and Precision Medicine Working Group assembled a group of international experts to propose recommendations for preparing clinical genomic reports for solid cancers. These recommendations aim to foster best practices in integrating genomic testing within clinical settings. After review of available evidence, several rounds of surveys and focused discussions were conducted to reach consensus on the recommendation statements. Only consensus recommendations were reported. Recommendation statements were graded in two tiers based on their clinical importance: level A (required to maintain common standards in reporting) and level B (optional but necessary to achieve ideal practice)., Results: Genomics reports should present key information in a front page(s) followed by supplementary information in one or more appendices. Reports should be structured into sections: (i) patient and sample details; (ii) assay and data analysis characteristics; (iii) sample-specific assay performance and quality control; (iv) genomic alterations and their functional annotation; (v) clinical actionability assessment and matching to potential therapy indications; and (vi) summary of the main findings. Specific recommendations to prepare each of these sections are made., Conclusions: We present a set of recommendations aimed at structuring genomics reports to enhance physician comprehension of genomic profiling results for solid cancers. Communication between ordering physicians and professionals reporting genomic data is key to minimise uncertainties and to optimise the impact of genomic tests in patient care., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Advancements in the field of precision medicine have prompted the European Society for Medical Oncology (ESMO) Precision Medicine Working Group to update the recommendations for the use of tumour next-generation sequencing (NGS) for patients with advanced cancers in routine practice., Methods: The group discussed the clinical impact of tumour NGS in guiding treatment decision using the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) considering cost-effectiveness and accessibility., Results: As for 2020 recommendations, ESMO recommends running tumour NGS in advanced non-squamous non-small-cell lung cancer, prostate cancer, colorectal cancer, cholangiocarcinoma, and ovarian cancer. Moreover, it is recommended to carry out tumour NGS in clinical research centres and under specific circumstances discussed with patients. In this updated report, the consensus within the group has led to an expansion of the recommendations to encompass patients with advanced breast cancer and rare tumours such as gastrointestinal stromal tumours, sarcoma, thyroid cancer, and cancer of unknown primary. Finally, ESMO recommends carrying out tumour NGS to detect tumour-agnostic alterations in patients with metastatic cancers where access to matched therapies is available., Conclusion: Tumour NGS is increasingly expanding its scope and application within oncology with the aim of enhancing the efficacy of precision medicine for patients with cancer., Competing Interests: Disclosure MFM reports receipt of a fee to institution as an invited speaker from Novartis; part-time employment in PEGASCY. CBW reports receipt of a fee for participation in Advisory Board from BMS, Celgene, Rafael, RedHill, Roche, Shire/Baxalta; receipt of a fee as an invited speaker from Amgen, AstraZeneca, Bayer, BMS, Celgene, Chugai, Falk, GSK, Janssen, Merck, MSD, Roche, Servier, Sirtex, Taiho; receipt of a fee for an expert testimony from Janssen; receipt of travel support from Bayer, Celgene, RedHill, Roche, Servier, Taiho; non-financial interest for receipt of research grant both personal and to institution from Roche; non-financial interest for serving as an officer in AIO—Arbeitsgemeinschaft Internistische Onkologie (Germany); non-financial interest for advisory role in EU Commission—DG RTD as a member of the EU Commission Mission Board for Cancer. ASt reports receipt of a fee for participation in Advisory Board from Aignostics, Amgen, AstraZeneca, Bayer, Eli Lilly, Illumina, Janssen, MSD, Pfizer, Seattle Genetics, Thermo Fisher; receipt of a fee to institution for participation in Advisory Board from BMS, Novartis, Takeda; receipt of a fee as an invited speaker from Incyte, Roche; receipt of research grant to institution from Bayer, BMS, Chugai, Incyte. FB reports receipt of a fee to institution for participation in Advisory Board from AbbVie, ACEA, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Eisai, Eli Lilly Oncology, F. Hoffmann-La Roche Ltd., Ignyta, Merck, Mirati, MSD, Novartis, Pfizer, Pierre Fabre, Sanofi Aventis, Seattle Genetics, Takeda; non-financial interest as a principal investigator from AstraZeneca, BMS, F. Hoffmann-La Roche Ltd., Innate Pharma, Merck, Mirati, Piere Fabre. AB reports receipt of a fee for participation in Advisory Board from Sanofi; receipt of a fee as an invited speaker from Roche. IB reports receipt of a fee as an invited speaker from AstraZeneca. JB reports receipt of a fee for participation in Advisory Board from BMS, Janssen, MSD; receipt of funding for study to institution from BMS. EC reports receipt of a fee for participation in Advisory Board from Astellas, AstraZeneca, Bayer, Daiichi Sankyo, Janssen, Eli Lilly, Medscape, MSD, Novartis, Pfizer; receipt of a fee as an invited speaker from Astellas, AstraZeneca, Clovis, Janssen, Medscape, Pfizer; receipt of funding to institution from AstraZeneca; receipt of research grants to institution from Bayer, Janssen, Pfizer; receipt of a fee to institution as a local principal investigator from Janssen, MSD, Pfizer. RD reports receipt of a fee for participation in Advisory Board from Foundation Medicine, Roche; receipt of a fee as an invited speaker from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Gilead, GlaxoSmithKline, Ipsen, Janssen, Libbs, Eli Lilly, Merck Sharp & Dohme, Roche, Sanofi, Servier, Takeda; part-time employment in Oncoclinicas; owning stocks/shares in Trialing; receipt of a research grant from Merck; receipt of research grants to institution from AstraZeneca, Daiichi Sankyo, GlaxoSmithKline, Novartis. AK reports receipt of a fee to institution for participation in Advisory Board from Roche; receipt of a fee as an invited speaker from Roche; funding to institution from Bristol Myers Squibb (BMS); non-financial interest as a principal investigator from Roche. AC reports receipt of a fee as an invited speaker from BMS, MSD, Novartis, Pierre Fabre. FMB reports receipt of a fee for participation in Advisory Board from Biovica, Eisai, Karyopharm, Protai, Seagen, Theratechnologies, Zentalis Pharmaceuticals; receipt of a fee for consultancy from AbbVie, AstraZeneca, Black Diamond Therapeutics, EcoR1, F. Hoffmann-La Roche Ltd., GT Aperion Therapeutics, Infinity Pharmaceuticals, Lengo Therapeutics, Loxo Oncology, Menarini Group, OnCusp Therapeutics, Seagen, Tallac Therapeutics, Zymeworks; non-financial interest as a coordinating principal investigator from AstraZeneca; non-financial interest as a local principal investigator from Aileron Therapeutics, AstraZeneca, Bayer Healthcare, Calithera Biosciences, Curis Inc., CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd., Debiopharm International, eFFECTOR Therapeutics, Genentech Inc., Guardant Health Inc., KLUS Pharma, Novartis, Taiho Pharmaceuticals Co.; receipt of research grants to institution from Aileron Therapeutics, AstraZeneca, Bayer Healthcare, CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd., eFFECTOR Therapeutics, Puma Biotechnology, Repare Therapeutics, Taiho Pharmaceuticals Co., Takeda Pharmaceuticals Co.; non-financial interest for serving as a Steering Committee Member from Genentech Inc.; receipt of travel support from Cholangiocarcinoma Foundation, European Organisation for Research and Treatment (EORTC), European Society for Medical Oncology (ESMO). SM reports receipt of a fee for participation in Advisory Board, Study Scientific Committee member from Roche, receipt of a fee as DSMB member from Biophytis, IQVIA, Kedrion Biopharma, Servier, Yuhan Corporation. RM reports receipt of a fee for participation in Advisory Board from GSK, AstraZeneca, Merck; receipt of a fee as an invited speaker from GSK, AstraZeneca, Clovis Oncology; receipt of a fee for expert testimony from Shionogi and Ellipses. NN reports receipt of a fee for participation in Advisory Board from Amgen, AstraZeneca, Bayer, Biocartis, Incyte, Novartis, Roche; receipt of a fee as an invited speaker from Eli Lilly, Illumina, Merck, MSD, Thermo Fisher, Roche, Novartis, Sophia Genetics, GSK, Servier; receipt of research grants to institution from AstraZeneca, Biocartis, Illumina, Incyte, Merck, QIAGEN, Roche, Thermo Fisher. JRF reports receipt of a fee for participation in Advisory Board from AstraZeneca, Bain Capital, Daiichi Sankyo, Merck, MultiplexDX, Inc., Paige.AI, Personalis, Repare Therapeutics, Roche Tissue Diagnostics; receipt of a fee for consulting from Eli Lilly, Goldman Sachs, Paige.AI, Repare Therapeutics, Saga Diagnostics; financial interest as a member of Board of Directors from Grupo Oncoclinicas, Odyssey Bio; owning stock options in Paige.AI, Repare Therapeutics; non-financial interest from a leadership role as a President of International Quality Network for Pathology (IQN Path) and a Past President of Italian Cancer Society (SIC). JR reports receipt of grants/research support from MSD, AstraZeneca; receipt of a fee to institution for participation in Advisory Board from AstraZeneca, EDIMARK; for conducting sponsored research to institution from Merck; receipt of a fee to institution as an invited speaker from AstraZeneca, Sanofi, Takeda, Janssen, Roche; non-financial interest for a leadership role as a Secretary of EORTC Lung Cancer Group. MR reports receipt of a fee for participation in Advisory Board from myMedEd; receipt of a fee as an invited speaker from Clinical Care Options, MJH Holdings, myMedEd, Physician’s Education Resource; receipt of a fee for review guideline pathways from Change Healthcare; receipt of a fee to institution as a local principal investigator from AstraZeneca, Merck, or co-principal investigator from Merck and local co-principal investigator from Pfizer; non-financial interest for serving as a Steering Committee Member from AstraZeneca, Merck; non-financial interest for advisory role in Tempus Labs, Zenith Pharmaceuticals; non-financial interest for providing editorial services for medical writing from AstraZeneca, Pfizer; non-financial interest as a member of ASCO. ER reports receipt of a fee to institution for participation in Advisory Board from Amgen, AstraZeneca, GSK, Roche; receipt of a fee to institution as an invited speaker from BMS, Clovis; receipt of funding for data base to institution from AstraZeneca. ASc reports receipt of a fee for participation in Advisory Board from Incyte; receipt of a fee as an invited speaker from Amgen, Aristea—MSD, Tesaro-GSK. CS reports receipt of a fee for participation in Advisory Board from Blueprint Medicines, Cogent Biosciences, Deciphera Pharmaceuticals, IDRx, Immunicum, New Bay; receipt of a fee as an invited speaker from Roche, PharmaMar; receipt of a fee as Steering Committee Member, both personal and to institution, from Deciphera, NewBay; receipt of research grants to institution from IDRx; receipt of travel grant from Bayer AG, Gilead, Pfizer, PharmaMar; non-financial interest as ESMO Faculty member and serving as a member of Board of Directors in the Spanish Group for Sarcoma Research (GEIS) and Spanish Society of Medical Oncology (SEOM). JM reports receipt of a fee for participation in Advisory Board from Amgen, Amunix Pharmaceuticals, AstraZeneca, Janssen, Pfizer, Roche; receipt of a fee to institution for participation in Advisory Board from Nuage Therapeutics; receipt of a fee as an invited speaker from AstraZeneca, GuardantHealth, MSD; receipt of research grants to institution from Amgen, AstraZeneca, Pfizer Oncology; non-financial interest from receiving product samples for access to drugs in early development for preclinical testing from AstraZeneca. FA reports receipt of a fee to institution for participation in Advisory Board from AstraZeneca, Boston Pharmaceutics, Daiichi Sankyo, Gilead, Guardant Health, Eli Lilly, N-Power Medicine, Novartis, Owkin, Pfizer, Roche, Servier; receipt of a personal fee for participation in Advisory Board from Lilly France; receipt of research grants to institution from AstraZeneca, Daiichi Sankyo, Guardant Health, Ely Lilly, Novartis, Owkin, Pfizer, Roche., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The treatment landscape of urothelial cancers has evolved in the last decade with the approval of chemotherapy, immune checkpoint inhibitors, targeted therapies, and antibody drug conjugates. Although improvements in response and survival have been achieved with these strategies, in some scenarios their benefit is still questionable. Current efforts to identify prognostic and predictive biomarkers are crucial for better patient selection and treatment outcomes. In this paper we will review the most promising biomarkers under investigation, such as molecular classifiers, genomic alterations, programmed cell death ligand 1 expression, tumor mutational burden, circulating tumor DNA, urinary biomarkers among others, for muscle invasive bladder cancer and metastatic urothelial cancers. Deeper understanding of these biomarkers will aid clinical decision-making and help tailor treatment strategies., Competing Interests: Declaration of competing interest All authors of this manuscript have directly participated in planning, execution, and/or analysis of this study. The contents of this manuscript have not been copyrighted or published previously. The contents of this manuscript are not now under consideration for publication elsewhere. The contents of this manuscript will not be copyrighted, submitted, or published elsewhere while acceptance by Urologic Oncology: Seminars and Original Investigations is under consideration. There are no directly related manuscripts or abstracts, published or unpublished, by any authors of this manuscript. No financial support or incentive has been provided for this manuscript. I am one author signing on behalf of all coauthors of this manuscript, and attesting to the above., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Metastatic colorectal cancer (mCRC) patients tend to have modest benefits from molecularly driven therapeutics. Patient-derived tumor organoids (PDTOs) represent an unmatched model to elucidate tumor resistance to therapy, due to their high capacity to resemble tumor characteristics., Materials and Methods: We used viable tumor tissue from two cohorts of patients with mCRC, naïve or refractory to treatment, respectively, for generating PDTOs. The derived models were subjected to a 6-day drug screening assay (DSA) with a comprehensive pipeline of chemotherapy and targeted drugs against almost all the actionable mCRC molecular drivers. For the second cohort DSA data were matched with those from PDTO genotyping., Results: A total of 40 PDTOs included in the two cohorts were derived from mCRC primary tumors or metastases. The first cohort included 31 PDTOs derived from patients treated in front line. For this cohort, DSA results were matched with patient responses. Moreover, RAS/BRAF mutational status was matched with DSA cetuximab response. Ten out of 12 (83.3%) RAS wild-type PDTOs responded to cetuximab, while all the mutant PDTOs, 8 out of 8 (100%), were resistant. For the second cohort (chemorefractory patients), we used part of tumor tissue for genotyping. Four out of nine DSA/genotyping data resulted applicable in the clinic. Two RAS-mutant mCRC patients have been treated with FOLFOX-bevacizumab and mitomycin-capecitabine in third line, respectively, based on DSA results, obtaining disease control. One patient was treated with nivolumab-second mitochondrial-derived activator of caspases mimetic (phase I trial) due to high tumor mutational burden at genotyping, experiencing stable disease. In one case, the presence of BRCA2 mutation correlated with DSA sensitivity to olaparib; however, the patient could not receive the therapy., Conclusions: Using CRC as a model, we have designed and validated a clinically applicable methodology to potentially inform clinical decisions with functional data. Undoubtedly, further larger analyses are needed to improve methodology success rates and propose suitable treatment strategies for mCRC patients., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Beyond programmed death-ligand 1 (PD-L1) assessed by the combined positive score (CPS) and tumor mutational burden (TMB), no other biomarkers are approved for immunotherapy interventions. Here, we investigated whether additional clinical and pathological variables may impact on immunotherapy outcomes in recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients., Methods: R/M HNSCC patients treated with immunotherapy were reviewed. Analyzed variables at baseline included: clinicopathological, laboratory, and variables reflecting the host nutritional status such as the prognostic nutritional index (PNI) and albumin. The primary endpoint was progression free survival (PFS). The secondary endpoints were overall survival (OS) and objective response rate (ORR). Univariable and multivariable Cox models were fitted and random forest algorithm was used to estimate the importance of each prognostic variable., Results: A total of 100 patients were treated with immunotherapy; 50% with single agent and 50% with experimental immunotherapy combinations. In the multivariable analysis, both ECOG performance status (HR: 1.73; 95%CI 1.07-2.82; p = 0.03) and PNI levels (10-point increments, HR: 0.66; 0.46-0.95; p = 0.03) were significantly associated with PFS. However, the derived neutrophil to lymphocyte ratio (dNLR) and lactate dehydrogenase (LDH) were not significantly associated with PFS (p-values > 0.15). In the OS analysis, albumin and PNI were the only statistically significant factors in the multivariable model (p < 0.001)., Conclusions: In our cohort, PNI and ECOG performance status were most strongly associated with PFS in R/M HNSCC patients treated with immunotherapy. These results suggest that parameters informative of nutritional status should be considered before immunotherapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: PD1/PD-L1 immune checkpoint inhibitors (ICI) have revolutionized cancer treatment. Although there is controversy about the accuracy of surrogate endpoints in the ICI setting to predict overall survival (OS), these endpoints are commonly used in confirmatory trials. Here we aimed to explore the validity of classical and novel surrogate endpoints in randomised controlled trials (RCT) that combine ICI plus chemotherapy (CT) in the first-line setting., Material and Methods: A systematic review was conducted to identify RCT investigating anti-PD1/PD-L1 drugs plus CT versus CT alone. We performed (i) arm-level analysis to evaluate predictors of median OS (mOS) and (ii) comparison-level analysis for OS hazard ratio (HR) estimations. Linear regression models weighted by trial size were fitted and adjusted R 2 values were reported., Results: Thirty-nine RCTs involving 22,341 patients met the inclusion criteria (17 non-small cell lung, 9 gastroesophageal and 13 in other cancers) with ten different ICI under study. Overall, ICI plus CT improved OS (HR = 0.76; 95%CI: 0.73-0.80). In the arm-level analysis, the best mOS prediction was obtained with a new endpoint that combines median duration of response and ORR (mDoR-ORR) and with median PFS (R 2  = 0.5 both). In the comparison-level analysis, PFS HR showed a moderate association with OS HR (R 2  = 0.52). Early OS read-outs were highly associated with final OS outcomes (R 2  = 0.80)., Conclusions: The association between surrogate endpoints and OS in first-line RCT combining anti-PD1/PD-L1 and CT is moderate-low. Early OS read-outs showed a good association with final OS HR while the mDOR-ORR endpoint could help to better design confirmatory trials after single-arm phase II trials., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: The addition of immune checkpoint inhibitors (ICI) to chemotherapy (CT) has been one of the main clinical research endeavors over the last few years in patients with metastatic triple-negative breast cancer (TNBC). Recent randomized controlled trials (RCTs) have presented heterogeneous results that have elicited discussion in the oncology community. Here we conducted a systematic review and meta-analysis to evaluate this strategy., Material and Methods: A systematic literature review was conducted to identify RCTs that evaluated the combination of ICI plus CT versus CT alone in untreated metastatic TNBC. Random effects models were used to estimate pooled hazard ratios (HR) and odds ratios with 95% confidence intervals (95 %CI)., Results: A total of three RCTs including 2,400 patients with TNBC met the eligibility criteria. Patients with PD-L1-positive tumors had a significantly better PFS with the addition of ICI (HR = 0.67; 95 %CI: 0.58-0.79) and a trend towards better OS (HR = 0.79; 95 %CI: 0.60-1.03), while no benefit was observed in patients with PD-L1-negative tumors. In the PD-L1-positive subgroup, no relevant differences were found according to taxane agent used, ECOG performance status or number of metastatic sites. However, CT naïve patients obtained a larger benefit with ICI (PFS HR = 0.53) than patients previously treated with CT in neoadjuvant/adjuvant setting (PFS HR = 0.81). The most frequent immune-related adverse events in patients receiving ICI were hypothyroidism (16%) and hyperthyroidism (4.9%)., Conclusions: ICI plus CT improves PFS and OS in PD-L1-positive population. A greater benefit in CT naïve patients was observed for the PD-L1-positive population while no difference was observed between taxane regimes used., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Current genetic and genomic tests measuring homologous recombination deficiency (HRD) show limited predictive value. This study compares the performance of an immunohistology-based RAD51 test with genetic/genomic tests to identify patients with HRD primary triple-negative breast cancer (TNBC) and evaluates its accuracy to select patients sensitive to platinum-based neoadjuvant chemotherapy (NACT)., Patients and Methods: This is a retrospective, blinded, biomarker analysis from the GeparSixto randomized clinical trial. TNBC patients received neoadjuvant paclitaxel plus Myocet®-nonpegylated liposomal doxorubicin (PM) or PM plus carboplatin (PMCb), both arms including bevacizumab. Formalin-fixed paraffin-embedded (FFPE) tumor samples were laid on tissue microarrays. RAD51, BRCA1 and γH2AX were quantified using an immunofluorescence assay. The predictive value of RAD51 was assessed by regression models. Concordance analyses were carried out between RAD51 score and tumor BRCA (tBRCA) status or genomic HRD score (Myriad myChoice®). Associations with pathological complete response (pCR) and survival were studied. Functional HRD was predefined as a RAD51 score ≤10% (RAD51-low)., Results: Functional HRD by RAD51-low was evidenced in 81/133 tumors (61%). RAD51 identified 93% tBRCA-mutated tumors and 45% non-tBRCA mutant cases as functional HRD. The concordance between RAD51 and genomic HRD was 87% [95% confidence interval (CI) 79% to 93%]. In patients with RAD51-high tumors, pCR was similar between treatment arms [PMCb 31% versus PM 39%, odds ratio (OR) 0.71, 0.23-2.24, P = 0.56]. Patients with RAD51-low tumors benefited from PMCb (pCR 66% versus 33%, OR 3.96, 1.56-10.05, P = 0.004; interaction test P = 0.02). This benefit maintained statistical significance in the multivariate analysis. Carboplatin addition showed similar disease-free survival in the RAD51-high [hazard ratio (HR) 0.40, log-rank P = 0.11] and RAD51-low (0.45, P = 0.11) groups., Conclusions: The RAD51 test identifies tumors with functional HRD and is highly concordant with tBRCA mutation and genomic HRD. RAD51 independently predicts clinical benefit from adding Cb to NACT in TNBC. Our results support further development to incorporate RAD51 testing in clinical decision-making., Competing Interests: Disclosure Personal fees and/or nonfinancial support from: Agendia (FM), Amgen (RD, MvM), AstraZeneca (JB, CD, MvM), Boehringer Ingelheim (RD), Celgene (FM), Chugai (SL), Clovis (FM), Daiichi-Sankyo (SL, CD), Genomic Health (MvM), GSK (FM), Immunomedics (FM), Ipsen (RD), Janssen-Cilag (FM), Libbs (RD), Lilly (FM), Merck-MSD (RD, FM, CD), Molecular Health (CD), Mylan (MvM), Novartis (FM, CD, MvM), Pfizer (FM, JB, MvM), Pierre Fabre (FM, MvM), Roche (RD, CD, MvM), Sanofi (RD), SeaGen (FM), Servier (RD). Research grants from: Abbvie (SL), Amgen (SL), AstraZeneca (SL, VS), Celgene (SL), Daiichi-Sankyo (SL), Merck (RD), Myriad Genetics (PJ, CD), Novartis (SL), Pierre Fabre (RD), Pfizer (SL), Roche (SL, CD), Tesaro (VS), Teva (SL), Vifor (SL), Immunomedics (SL). Other funding paid to institution from: BMS (SL), Eirgenix (SL), Lilly (SL), Merck (SL), MSD (SL), SeaGen (SL), Prime/Medscape (SL), Puma (SL), Samsung (SL), Pierre Fabre (SL). Stock ownership from: Myriad Genetics (PJ), Sividon Diagnostics (CD until 2016). Patents and other intellectual property: WO2019122411A1 (ALG, JB, VS), EP14153692.0 (SL), VMScope digital pathology software (CD), WO2015114146A1 (CD), WO2010076322A1 (CD), WO2020109570A1 (CD). All remaining authors have declared no conflicts of interest., (Copyright © 2021 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Background: The COVID-19 pandemic has impacted all aspects of modern-day oncology, including how stakeholders communicate through social media. We surveyed oncology stakeholders in order to assess their attitudes pertaining to social media and how it has been affected during the pandemic., Materials and Methods: A 40-item survey was distributed to stakeholders from 8 July to 22 July 2020 and was promoted through the European Society for Medical Oncology (ESMO) and the OncoAlert Network., Results: One thousand and seventy-six physicians and stakeholders took part in the survey. In total, 57.3% of respondents were medical oncologists, 50.6% aged <40 years, 50.8% of female gender and mostly practicing in Europe (51.5%). More than 90% of respondents considered social media a useful tool for distributing scientific information and for education. Most used social media to stay up to date on cancer care in general (62.5%) and cancer care during COVID-19 (61%) given the constant flow of information. Respondents also used social media to interact with other oncologists (78.8%) and with patients (34.4%). Overall, 61.1% of respondents were satisfied with the role that social media was playing during the COVID-19 pandemic. On the other hand, 41.1% of respondents reported trouble in discriminating between credible and less credible information and 30% stated social networks were a source of stress. For this reason, one-third of respondents reduced its use during the COVID-19 pandemic. Regarding meeting attendance, a total of 59.1% of responding physicians preferred in-person meetings to virtual ones, and 51.8% agreed that virtual meetings and social distancing could hamper effective collaboration., Conclusion: Social media has a useful role in supporting cancer care and professional engagement in oncology. Although one-third of respondents reported reduced use of social media due to stress during the COVID-19 pandemic, the majority found social media useful to keep up to date and were satisfied with the role social media was playing during the pandemic., Competing Interests: Disclosure ML acted as a consultant for Roche, Novartis, AstraZeneca and Lilly and received speaker honoraria from Roche, Novartis, Lilly, Pfizer, Takeda and Sandoz. MT declares travel, accommodation, expenses supported by Roche, Bristol-Myers Squibb, AstraZeneca, Takeda, and activity as a medical writer supported by Novartis and Amgen. AL declares travel and educational support from Ipsen, Pfizer, Bayer, AAA, Sirtex, Novartis, Mylan and Delcath; speaker honoraria from Merck, Pfizer, Ipsen, Incyte and AAA; advisory honoraria from EISAI, Nutricia Ipsen, QED and Roche; she is a member of the NETCONNECT Initiative funded by Ipsen; all these are outside the scope of the present work. SPilotto acted as a consultant for AstraZeneca, BMS, Boehringer Ingelheim, MSD and Roche, and received speaker honoraria from AstraZeneca, BMS, Boehringer Ingelheim, MSD and Roche, outside the scope of the present work. CC received honoraria for speaker, consultancy or advisory role from Roche, Novartis, Pfizer, Eli Lilly, and MSD. RD has declared advisory roles for Roche, Boehringer Ingelheim and Bayer, has received a speaker's fee from Roche, Ipsen, Amgen, Servier, Sanofi, Merck Sharp and Dohme, and research grants from Merck and Pierre Fabre. MScheffler Advisory role, speaker: Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Novartis, Pfizer, Roche, Takeda. Personal research support: Amgen, Dracen Pharmaceuticals. BW received personal and speaker fees, reimbursements for travel and accommodation and honoraria for participation in advisory boards from Bayer, BMS, Celgene, GSK, Ipsen, Shire/Baxalta, Sirtex and Taiho and a scientific grant supported by Roche. AC: Honoraria/consulting or advisory role: AstraZeneca, Boehringer Ingelheim, Pfizer, Roche/Genentech, Eli Lilly and Company, Takeda, Novartis, Merck Sharp and Dohme and Bristol-Myers Squibb. SPeters has received education grants, provided consultation, attended advisory boards and/or provided lectures for the following organizations, from whom I have received honoraria (all fees to institution): consultation/advisory role: AbbVie, Amgen, AstraZeneca, Bayer, BeiGene, Biocartis, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, F. Hoffmann-La Roche, Foundation Medicine, Illumina, Incyte, Janssen, Medscape, Merck Sharp and Dohme, Merck Serono, Merrimack, Novartis, Pharma Mar, Phosplatin Therapeutics, Pfizer, Regeneron, Sanofi, Seattle Genetics, Takeda. Talk in a company's organized public event: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Illumina, Medscape, Merck Sharp and Dohme, Novartis, Pfizer, Prime, Sanofi, Takeda. Receipt of grants/research supports: (sub)investigator in trials (institutional financial support for clinical trials) sponsored by Amgen, AstraZeneca, Biodesix, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, F. Hoffmann-La Roche, GSK, Illumina, Lilly, Merck Sharp and Dohme, Merck Serono, Mirati, Novartis, and Pfizer, Phosplatin Therapeutics. EdA reports having received honoraria and advisory board for Roche/GNE, Novartis, Seattle Genetics, Zodiac, Lubbs and Pierre Fabre. He reports having received travel grants from Roche/GNE, GSK, and Novartis. He reports having received institutional grants for his institute from Roche/GNE, AstraZeneca, Novartis and Servier outside the submitted work. All other authors have declared no conflicts of interest., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Next-generation sequencing (NGS) allows sequencing of a high number of nucleotides in a short time frame at an affordable cost. While this technology has been widely implemented, there are no recommendations from scientific societies about its use in oncology practice. The European Society for Medical Oncology (ESMO) is proposing three levels of recommendations for the use of NGS. Based on the current evidence, ESMO recommends routine use of NGS on tumour samples in advanced non-squamous non-small-cell lung cancer (NSCLC), prostate cancers, ovarian cancers and cholangiocarcinoma. In these tumours, large multigene panels could be used if they add acceptable extra cost compared with small panels. In colon cancers, NGS could be an alternative to PCR. In addition, based on the KN158 trial and considering that patients with endometrial and small-cell lung cancers should have broad access to anti-programmed cell death 1 (anti-PD1) antibodies, it is recommended to test tumour mutational burden (TMB) in cervical cancers, well- and moderately-differentiated neuroendocrine tumours, salivary cancers, thyroid cancers and vulvar cancers, as TMB-high predicted response to pembrolizumab in these cancers. Outside the indications of multigene panels, and considering that the use of large panels of genes could lead to few clinically meaningful responders, ESMO acknowledges that a patient and a doctor could decide together to order a large panel of genes, pending no extra cost for the public health care system and if the patient is informed about the low likelihood of benefit. ESMO recommends that the use of off-label drugs matched to genomics is done only if an access programme and a procedure of decision has been developed at the national or regional level. Finally, ESMO recommends that clinical research centres develop multigene sequencing as a tool to screen patients eligible for clinical trials and to accelerate drug development, and prospectively capture the data that could further inform how to optimise the use of this technology., Competing Interests: Disclosure JR: advisory: Merck Sharp & Dohme (MSD), Boehringer, Bristol-Myers Squibb (BMS), AstraZeneca, Roche; speaker's bureau: Pfizer; travel support: OSE Immunotherapeutics SA, BMS, AstraZeneca, Roche. JM: advisory board: Amgen, AstraZeneca, Clovis Oncology, Janssen, MSD and Roche-Foundation Medicine; research funding: AstraZeneca and Pfizer Oncology; principal investigator of several industry sponsored clinical trials. CBW: personal and speakers' fees, reimbursement for travel and accommodation and honoraria for participance in advisory boards from Bayer, Celgene, Ipsen, MedScape, Rafael Pharmaceuticals, RedHill, Roche, Servier, Shire/Baxalta and Taiho; scientific grant support by Roche. FB: personal fees from AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer–Ingelheim, Eli Lilly Oncology, F. Hoffmann–La Roche Ltd, Novartis, Merck, MSD, Pierre Fabre, Pfizer and Takeda. MPL: research grants (to hospital): MSD, Astellas, JnJ, Sanofi; advice: Roche, Bayer, Amgen, JnJ, Sanofi, Servier, Pfizer, Incyte. NN: speaker's fee and/or advisory boards: Amgen, AstraZeneca, Bayer, Biocartis, BMS, Boehringer Ingelheim, Eli Lilly, Ilumina, Incyte, MERCK, MSD, Qiagen, Roche, Thermofisher, Sanofi; institutional financial interests (financial support to research projects): AstraZeneca, Biocartis, BMS, Illumina, Merck, Qiagen, Roche, Sysmex, Thermofisher; non-financial interests: President of the International Quality Network for Pathology (IQN Path); President of the Italian Cancer Society (SIC). ASc: speakers bureau: Ypsen, Astra Zeneca, Amgen, MSD, GSK; consulting: INCYTE Biosciences. MR: consulting or advisory: AstraZeneca (uncompensated), Change Healthcare, Daiichi-Sankyo (uncompensated), Epic Sciences (uncompensated), Merck (uncompensated), Pfizer (uncompensated); research funding: AbbVie (institution), AstraZeneca (Institution), Invitae (Institution, in-kind), Merck (Institution), Pfizer (institution); travel, accommodation, expenses: AstraZeneca, Merck; editorial services: AstraZeneca, Pfizer. FM-B: consulting: Aduro BioTech Inc., Alkermes, DebioPharm, eFFECTOR Therapeutics, F. Hoffman-La Roche Ltd, Genentech Inc., IBM Watson, Jackson Laboratory, Kolon Life Science, OrigiMed, PACT Pharma, Parexel International, Pfizer Inc., Samsung Bioepis, Seattle Genetics Inc., Tyra Biosciences, Xencor, Zymeworks; advisory committee: Immunomedics, Inflection Biosciences, Mersana Therapeutics, Puma Biotechnology Inc., Seattle Genetics, Silverback Therapeutics, Spectrum Pharmaceuticals, Zentalis; sponsored research: Aileron Therapeutics, Inc., AstraZeneca, Bayer Healthcare Pharmaceutical, Calithera Biosciences Inc., Curis Inc., CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd, Debiopharm International, eFFECTOR Therapeutics, Genentech Inc., Guardant Health Inc., Millennium Pharmaceuticals Inc., Novartis, Puma Biotechnology Inc., Taiho Pharmaceutical Co.; honoraria: Chugai Biopharmaceuticals, Mayo Clinic, Rutgers Cancer Institute of New Jersey; other (Travel Related): Beth Israel Deaconess Medical Center. NW: research grant from Puma Biotechnology; scientific advisory board and stockholder for Relay Therapeutics; advisor to Eli Lilly. ASt: advisory board/speakers bureau: Astra Zeneca, Eli Lilly, Bayer, BMS, Illumina, Janssen, MSD, Pfizer, Roche, Seattle Genetics, Thermo Fisher; Grants: Bayer, BMS, Chugai. JB: travel support: BMS; consulting fees: BMS, MSD, Astellas. SM: statistical advice: IDDI and Janssen Cilag; Independent Data Monitoring Committee member: Hexal, Steba, IQVIA, Roche, Sensorion, Biophytis, Servier, Yuhan. IB: speaker’s fee: AstraZeneca. ER: board participation: AstraZeneca, BMS, Roche; travel funding: AstraZeneca, BMS. JSR-F: paid consultant: Goldman Sachs, REPARE Therapeutics, and Paige.AI; member of the scientific advisory board: REPARE Therapeutics, Paige.AI, and Volition Rx; member of the Board of Directors: Group Oncoclinicas; ad hoc member of the scientific advisory board: Roche Tissue Diagnostics, Roche, Genentech, Novartis, and Invicro; owns shares: REPARE Therapeutics. RD: advisory: Roche, Boehringer Ingelheim; speaker’s fee: Roche, Ipsen, Amgen, Servier, Sanofi, Merck Sharp & Dohme; research grants: Merck and Pierre Fabre. FA: research grants and talks/advisory boards compensate to the hospital: Roche, Pfizer, Novartis, AstraZeneca, Daiichi Sankyo, Lilly. All remaining authors have declared no conflicts of interest., (Copyright © 2020 European Society for Medical Oncology. All rights reserved.)

Background: Accumulating evidence has identified Fusobacterium as an important pathogenic gut bacterium associated with colorectal cancer. Nevertheless, only limited data exist about the role of this bacterium in locally advanced rectal cancer (LARC). In this study, we quantified Fusobacterium nucleatum in untreated and post-neoadjuvant chemoradiotherapy (nCRT) samples from LARC patients and investigated its association with therapy response and survival., Patients and Methods: A total of 254 samples from 143 patients with rectal adenocarcinomas were analyzed for the presence and abundance of F. nucleatum using RNA in situ hybridization and digital image analysis. Assay accuracy was determined using infected cell lines and tumor samples with available quantitative PCR data. We studied the impact of F. nucleatum load on pathologic complete response and relapse-free survival. Treatment-induced changes were evaluated in paired pre- and post-nCRT samples (n = 71). Finally, tumor microenvironment changes during nCRT were assessed in paired samples (n = 45) by immune contexture analysis., Results: F. nucleatum tissue levels by RNA in situ hybridization strongly correlated with quantitative PCR (r = 0.804, P < 0.001). F. nucleatum abundance was higher in untreated [median, 7.4; 95% confidence interval (3.7-16.2)] compared with treated [median, 1.6; 95% confidence interval (1.3-2.4)] tumors (P <0.001) with 58% (73/126) and 26% (22/85) positive tumors, respectively (P < 0.001). Baseline F. nucleatum levels were not associated with pathologic complete response. F. nucleatum positivity after nCRT, but not baseline status, significantly increased risk of relapse [hazard ratio = 7.5, 95% confidence interval (3.0-19.0); P < 0.001]. Tumors that turned F. nucleatum-negative after nCRT had a strong increase in CD8+ T cells post-nCRT (P < 0.001), while those that persisted F. nucleatum-positive after nCRT lacked CD8+ T cells induction in post-nCRT samples compared with baseline (P = 0.69)., Conclusion: F. nucleatum persistence post-nCRT is associated with high relapse rates in LARC, potentially linked to suppression of immune cytotoxicity., Competing Interests: Disclosure JT reports personal financial interest in the form of scientific consultancy role for Array Biopharma, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Chugai, Genentech, Inc., Genmab A/S, Halozyme, Imugene Limited, Inflection Biosciences Limited, Ipsen, Kura Oncology, Lilly, Merck Sharp & Dohme, Menarini, Merck Serono, Merrimack, Merus, Molecular Partners, Novartis, Peptomyc, Pfizer, Pharmacyclics, ProteoDesign SL, Rafael Pharmaceuticals, F. Hoffmann-La Roche Ltd, Sanofi, SeaGen, Seattle Genetics, Servier, Symphogen, Taiho, VCN Biosciences, Biocartis, Foundation Medicine, HalioDX SAS, and Roche Diagnostics. JC reports scientific consultancy role (speaker and advisory roles) from Novartis, Pfizer, Ipsen, Exelixis, Bayer, Eisai, Advanced Accelerator Applications, Amgen, Sanofi, ITM, Sirlex and Merck Serono. Research grants from Novartis, Pfizer, AstraZeneca, Advanced Accelerator Applications, Eisai, and Bayer. RD has an advisory role at Roche and Boehringer-Ingelheim, has received a speaker’s fee from Roche, Ipsen, Amgen, Sanofi, Servier, Merck Sharp & Dohme and further received direct research funding from Merck and Pierre Fabre. PN has consulted for Bayer, Novartis, Merck Sharp & Dohme, and Targos, and received compensation. The other authors have declared no conflicts of interest., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: It remains unknown to what extent consensus molecular subtype (CMS) groups and immune-stromal infiltration patterns improve our ability to predict outcomes over tumor-node-metastasis (TNM) staging and microsatellite instability (MSI) status in early-stage colorectal cancer (CRC)., Patients and Methods: We carried out a comprehensive retrospective biomarker analysis of prognostic markers in adjuvant chemotherapy-untreated (N = 1656) and treated (N = 980), stage II (N = 1799) and III (N = 837) CRCs. We defined CMS scores and estimated CD8+ cytotoxic lymphocytes (CytoLym) and cancer-associated fibroblasts (CAF) infiltration scores from bulk tumor tissue transcriptomes (CMSclassifier and MCPcounter R packages); constructed a stratified multivariable Cox model for disease-free survival (DFS); and calculated the relative proportion of explained variation by each marker (clinicopathological [ClinPath], genomics [Gen: MSI, BRAF and KRAS mutations], CMS scores [CMS] and microenvironment cells [MicroCells: CytoLym+CAF])., Results: In multivariable models, only ClinPath and MicroCells remained significant prognostic factors, with both CytoLym and CAF infiltration scores improving survival prediction beyond other markers. The explained variation for DFS models of ClinPath, MicroCells, Gen markers and CMS4 scores was 77%, 14%, 5.3% and 3.7%, respectively, in stage II; and 55.9%, 35.1%, 4.1% and 0.9%, respectively, in stage III. Patients whose tumors were CytoLym high/CAF low had better DFS than other strata [HR=0.71 (0.6-0.9); P = 0.004]. Microsatellite stable tumors had the strongest signal for improved outcomes with CytoLym high scores (interaction P = 0.04) and the poor prognosis linked to high CAF scores was limited to stage III disease (interaction P = 0.04)., Conclusions: Our results confirm that tumor microenvironment infiltration patterns represent potent determinants of the risk for distant dissemination in early-stage CRC. Multivariable models suggest that the prognostic value of MSI and CMS groups is largely explained by CytoLym and CAF infiltration patterns., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)

Objectives: Aberrant PI3K/AKT/mTOR activation is common in gynaecological malignancies. However, predictive biomarkers of response to PI3K pathway inhibitors (PAMi) have yet to be identified., Methods: We analysed the outcomes of patients with advanced gynaecological cancer with available genomic data, treated with PAMi as single agents or in combination in phase I clinical trials. Clinical relevance of the PIK3CA mutant allele fraction (MAF) was investigated. MAF of each variant was normalised for tumour purity in the sample (adjMAFs) to infer clonality of PIK3CA mutations, defined as clonal (≥0.4) or subclonal (<0.4)., Results: A total of 50 patients with gynaecological cancer (24 ovarian; 15 endometrial; 11 cervical) with available targeted mutation profiling were selected. PAMi therapy was matched to PIK3CA/PTEN mutation in 30 patients (60%). The overall response rate, median time to progression (mTTP) and clinical benefit rate (CBR) of the entire population were 10% (N=5), 3.57 months (2.57-4.4) and 40% (N=18), respectively. Genotype-matched therapy did not lead to a favourable CBR (OR 0.91, p=1 (0.2-3.7)) or mTTP (3.57 months (2.6-4.4) vs 3.73 months (1.9-13.2); HR 1.41; p=0.29). We did not detect differences in mTTP according to therapy or PIK3CA codon mutation (HR 1.71, p=0.24). Overall, 41% of patients had a TTP ratio (TTP PAMi/TTP on immediately prior or subsequent palliative chemotherapy) ≥1.3, without statistically significant differences according to tumour type (p=0.39), molecular alteration status (p=0.13) or therapy (p=0.54). In univariate analysis, genotype-matched therapy in patients with PIK3CA clonal events was associated with improved mTTP (HR 3.6; p=0.03)., Conclusions: Our study demonstrates that patients with advanced gynaecological cancer, refractory to standard therapies, achieved meaningful clinical benefit from PAMi. The impact of PI3KCA clonality on response to selected PAMi in patients with gynaecological cancer deserves further investigation., Competing Interests: Competing interests: AO is a consultant/advisory board member of AstraZeneca, Clovis, Tesaro, Roche and PharmaMar. RD reports personal fees from Roche, outside the submitted work.

Precision oncology based on next-generation sequencing (NGS) test is growing in daily clinical practice. However, the real impact of this strategy in patients' outcome on a large scale remains uncertain. In this review, we summarise existing literature on this topic, limitations for broad NGS implementation, bottlenecks in genomic variant interpretation and the role of molecular tumour boards., Competing Interests: Competing interests: None declared.

Background: Gene expression-based profiling of colorectal cancer (CRC) can be used to identify four molecularly homogeneous consensus molecular subtype (CMS) groups with unique biologic features. However, its applicability to colorectal premalignant lesions remains unknown., Patients and Methods: We assembled the largest transcriptomic premalignancy dataset by integrating different public and proprietary cohorts of adenomatous and serrated polyps from sporadic (N = 311) and hereditary (N = 78) patient populations and carried out a comprehensive analysis of carcinogenesis pathways using the CMS random forest (RF) classifier., Results: Overall, transcriptomic subtyping of sporadic and hereditary polyps revealed CMS2 and CMS1 subgroups as the predominant molecular subtypes in premalignancy. Pathway enrichment analysis showed that adenomatous polyps from sporadic or hereditary cases (including Lynch syndrome) displayed a CMS2-like phenotype with WNT and MYC activation, whereas hyperplastic and serrated polyps with CMS1-like phenotype harbored prominent immune activation. Rare adenomas with CMS4-like phenotype showed significant enrichment for stromal signatures along with transforming growth factor-β activation. There was a strong association of CMS1-like polyps with serrated pathology, right-sided anatomic location and BRAF mutations., Conclusions: Based on our observations made in premalignancy, we propose a model of pathway activation associated with CMS classification in colorectal carcinogenesis. Specifically, while adenomatous polyps are largely CMS2, most hyperplastic and serrated polyps are CMS1 and may transition into other CMS groups during evolution into carcinomas. Our findings shed light on the transcriptional landscape of premalignant colonic polyps and may help guide the development of future biomarkers or preventive treatments for CRC.

Background: In order to facilitate implementation of precision medicine in clinical management of cancer, there is a need to harmonise and standardise the reporting and interpretation of clinically relevant genomics data., Methods: The European Society for Medical Oncology (ESMO) Translational Research and Precision Medicine Working Group (TR and PM WG) launched a collaborative project to propose a classification system for molecular aberrations based on the evidence available supporting their value as clinical targets. A group of experts from several institutions was assembled to review available evidence, reach a consensus on grading criteria and present a classification system. This was then reviewed, amended and finally approved by the ESMO TR and PM WG and the ESMO leadership., Results: This first version of the ESMO Scale of Clinical Actionability for molecular Targets (ESCAT) defines six levels of clinical evidence for molecular targets according to the implications for patient management: tier I, targets ready for implementation in routine clinical decisions; tier II, investigational targets that likely define a patient population that benefits from a targeted drug but additional data are needed; tier III, clinical benefit previously demonstrated in other tumour types or for similar molecular targets; tier IV, preclinical evidence of actionability; tier V, evidence supporting co-targeting approaches; and tier X, lack of evidence for actionability., Conclusions: The ESCAT defines clinical evidence-based criteria to prioritise genomic alterations as markers to select patients for targeted therapies. This classification system aims to offer a common language for all the relevant stakeholders in cancer medicine and drug development.

Background: The prognostic impact of KRAS and BRAFV600E mutations in primary colorectal cancer (CRC) varies with microsatellite instability (MSI) status. The gene expression-based consensus molecular subtypes (CMSs) of CRC define molecularly and clinically distinct subgroups, and represent a novel stratification framework in biomarker analysis. We investigated the prognostic value of these mutations within the CMS groups., Patients and Methods: Totally 1197 primary tumors from a Norwegian series of CRC stage I-IV were analyzed for MSI and mutation status in hotspots in KRAS (codons 12, 13 and 61) and BRAF (codon 600). A subset was analyzed for gene expression and confident CMS classification was obtained for 317 samples. This cohort was expanded with clinical and molecular data, including CMS classification, from 514 patients in the publically available dataset GSE39582. Gene expression signatures associated with KRAS and BRAFV600E mutations were used to evaluate differential impact of mutations on gene expression among the CMS groups., Results: BRAFV600E and KRAS mutations were both associated with inferior 5-year overall survival (OS) exclusively in MSS tumors (BRAFV600E mutation versus KRAS/BRAF wild-type: Hazard ratio (HR) 2.85, P < 0.001; KRAS mutation versus KRAS/BRAF wild-type: HR 1.30, P = 0.013). BRAFV600E-mutated MSS tumors were strongly enriched and associated with metastatic disease in CMS1, leading to negative prognostic impact in this subtype (OS: BRAFV600E mutation versus wild-type: HR 7.73, P = 0.001). In contrast, the poor prognosis of KRAS mutations was limited to MSS tumors with CMS2/CMS3 epithelial-like gene expression profiles (OS: KRAS mutation versus wild-type: HR 1.51, P = 0.011). The subtype-specific prognostic associations were substantiated by differential effects of BRAFV600E and KRAS mutations on gene expression signatures according to the MSI status and CMS group., Conclusions: BRAFV600E mutations are enriched and associated with metastatic disease in CMS1 MSS tumors, leading to poor prognosis in this subtype. KRAS mutations are associated with adverse outcome in epithelial (CMS2/CMS3) MSS tumors.

Background: Circulating tumor DNA (ctDNA) is a potential source for tumor genome analysis. We explored the concordance between the mutational status of RAS in tumor tissue and ctDNA in metastatic colorectal cancer (mCRC) patients to establish eligibility for anti-epidermal growth factor receptor (EGFR) therapy., Patients and Methods: A prospective-retrospective cohort study was carried out. Tumor tissue from 146 mCRC patients was tested for RAS status with standard of care (SoC) PCR techniques, and Digital PCR (BEAMing) was used both in plasma and tumor tissue., Results: ctDNA BEAMing RAS testing showed 89.7% agreement with SoC (Kappa index 0.80; 95% CI 0.71 - 0.90) and BEAMing in tissue showed 90.9% agreement with SoC (Kappa index 0.83; 95% CI 0.74 - 0.92). Fifteen cases (10.3%) showed discordant tissue-plasma results. ctDNA analysis identified nine cases of low frequency RAS mutations that were not detected in tissue, possibly due to technical sensitivity or heterogeneity. In six cases, RAS mutations were not detected in plasma, potentially explained by low tumor burden or ctDNA shedding. Prediction of treatment benefit in patients receiving anti-EGFR plus irinotecan in second- or third-line was equivalent if tested with SoC PCR and ctDNA. Forty-eight percent of the patients showed mutant allele fractions in plasma below 1%., Conclusions: Plasma RAS determination showed high overall agreement and captured a mCRC population responsive to anti-EGFR therapy with the same predictive level as SoC tissue testing. The feasibility and practicality of ctDNA analysis may translate into an alternative tool for anti-EGFR treatment selection., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: TNM staging alone does not accurately predict outcome in colon cancer (CC) patients who may be eligible for adjuvant chemotherapy. It is unknown to what extent the molecular markers microsatellite instability (MSI) and mutations in BRAF or KRAS improve prognostic estimation in multivariable models that include detailed clinicopathological annotation., Patients and Methods: After imputation of missing at random data, a subset of patients accrued in phase 3 trials with adjuvant chemotherapy (n = 3016)-N0147 (NCT00079274) and PETACC3 (NCT00026273)-was aggregated to construct multivariable Cox models for 5-year overall survival that were subsequently validated internally in the remaining clinical trial samples (n = 1499), and also externally in different population cohorts of chemotherapy-treated (n = 949) or -untreated (n = 1080) CC patients, and an additional series without treatment annotation (n = 782)., Results: TNM staging, MSI and BRAFV600E mutation status remained independent prognostic factors in multivariable models across clinical trials cohorts and observational studies. Concordance indices increased from 0.61-0.68 in the TNM alone model to 0.63-0.71 in models with added molecular markers, 0.65-0.73 with clinicopathological features and 0.66-0.74 with all covariates. In validation cohorts with complete annotation, the integrated time-dependent AUC rose from 0.64 for the TNM alone model to 0.67 for models that included clinicopathological features, with or without molecular markers. In patient cohorts that received adjuvant chemotherapy, the relative proportion of variance explained (R2) by TNM, clinicopathological features and molecular markers was on an average 65%, 25% and 10%, respectively., Conclusions: Incorporation of MSI, BRAFV600E and KRAS mutation status to overall survival models with TNM staging improves the ability to precisely prognosticate in stage II and III CC patients, but only modestly increases prediction accuracy in multivariable models that include clinicopathological features, particularly in chemotherapy-treated patients., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)

Background: As novel treatments carry substantial price tags and are mostly cost-prohibitive in low- and middle-income countries, there is an urgent need to develop alternatives, such as off-patent drugs. Megestrol acetate (MA) has a longstanding history in the treatment of breast cancer, but recently it is being used less often due to the advent of newer agents., Patients and Methods: This two-stage phase II trial evaluated the antitumor activity and toxicity of MA in postmenopausal women with hormone-sensitive advanced breast cancer who had experienced disease progression on a third-generation nonsteroidal aromatase inhibitor (NSAI). Eligible patients had metastatic breast cancer treated with a NSAI with at least 6-month progression-free survival (PFS), or relapse after ≥1 year on adjuvant NSAI. Patients received MA at a single daily oral dose of 160 mg. Primary end point was clinical benefit rate (CBR)., Results: Forty-eight patients were enrolled. The CBR was 40% [95% confidence interval (CI) 25% to 55%], and the median duration of clinical benefit was 10.0 (95% CI 8.0-14.2) months. The median PFS was 3.9 (95% CI 3.0-4.8) months. The most common grade 3 adverse events were anemia (2%), dyspnea (2%), fatigue (2%), musculoskeletal pain (4%), deep vein thrombosis (10%), and weight gain (2%)., Conclusions: This is the first study to prospectively evaluate the efficacy and safety of MA in postmenopausal women with hormone-sensitive disease progressing on a NSAI. MA has demonstrated activity and acceptable tolerability in this setting, and therefore remains a reasonable treatment option in a cost-sensitive environment. These results also provide the background for further evaluation of progestins in the treatment of breast cancer., Clinical Trials: local trial number, related to the approval by the IRB: CEP 108/06.

The fibroblast growth factor receptor (FGFR) cascade plays crucial roles in tumor cell proliferation, angiogenesis, migration and survival. Accumulating evidence suggests that in some tumor types, FGFRs are bona fide oncogenes to which cancer cells are addicted. Because FGFR inhibition can reduce proliferation and induce cell death in a variety of in vitro and in vivo tumor models harboring FGFR aberrations, a growing number of research groups have selected FGFRs as targets for anticancer drug development. Multikinase FGFR/vascular endothelial growth factor receptor (VEGFR) inhibitors have shown promising activity in breast cancer patients with FGFR1 and/or FGF3 amplification. Early clinical trials with selective FGFR inhibitors, which may overcome the toxicity constraints raised by multitarget kinase inhibition, are recruiting patients with known FGFR(1-4) status based on genomic screens. Preliminary signs of antitumor activity have been demonstrated in some tumor types, including squamous cell lung carcinomas. Rational combination of targeted therapies is expected to further increase the efficacy of selective FGFR inhibitors. Herein, we discuss unsolved questions in the clinical development of these agents and suggest guidelines for management of hyperphosphatemia, a class-specific mechanism-based toxicity. In addition, we propose standardized definitions for FGFR1 and FGFR2 gene amplification based on in situ hybridization methods. Extended access to next-generation sequencing platforms will facilitate the identification of diseases in which somatic FGFR(1-4) mutations, amplifications and fusions are potentially driving cancer cell viability, further strengthening the role of FGFR signaling in cancer biology and providing more possibilities for the therapeutic application of FGFR inhibitors.

Colorectal cancer is a leading cause of cancer mortality despite recent expansion of treatment options in metastatic colorectal cancer (mCRC). Our knowledge about key signaling pathways in colorectal tumors has contributed to the identification of specific molecular markers of response to targeted agents. In this review we discuss well-established and potential predictive biomarkers of benefit with epidermal growth factor receptor (EGFR) inhibitors. Data derived from multiple phase III trials have indicated that KRAS mutations can be considered a highly specific negative biomarker of response to anti-EGFR monoclonal antibodies. Other molecular aberrations in pathways downstream of EGFR such as BRAF, NRAS, and PIK3CA mutations, and PTEN loss are also reviewed. Moreover biomarkers of efficacy to classic chemotherapeutic agents as well as recent advances regarding high-throughput technologies and circulating tumor cells are also considered. Personalized cancer medicine in the mCRC scenario seems to be near reality, but validation of many biomarkers in prospective clinical trials is urgently warranted., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: The aim of this study was to investigate whether mRNA expression of the apoptosis-associated genes, XAF1 and XIAP, in bladder cancer patients correlates with response to neoadjuvant treatment., Methods: Gene expression was analyzed by a real-time quantitative PCR method in paired samples from 14 bladder cancer patients treated with a combination of neoadjuvant gemcitabine and cisplatin. The prognostic significance of XAF1 and XIAP mRNA expression as well as the correlation with several clinical and pathological findings were evaluated., Results: The clinical response in the XAF1-high subset (n = 5) was remarkably higher compared with the XAF1-low subset (n = 9) (100% vs. 44.4%; P = 0.038). These results translated into a notably improvement of progression-free survival (PFS) in the XAF1-high subset (log-rank P = 0.012). In addition, patients in the XAF1-high subset had a 3.9-fold decreased chance of dying from the disease (hazard ratio for death (HR), 0.257; (CI 95%), 0.043-1.536, P = 0.036). When we evaluated the expression of XIAP, although an inverse correlation was found between expression and pathological response, there were no statistically significant associations with the clinical response, the length of PFS, and OS., Conclusions: This is one of the few studies to address the role of XAF1 in a clinical setting. The data presented here identify XAF1 as a novel predictive and prognostic factor in bladder cancer patients. Furthermore, our observations are in line with previous studies, which point towards XAF1 as a tumor-suppressor gene. Nonetheless, additional studies, both mechanistic and translational, are warranted and may help not only in corroborating the role of XAF1 as a prognostic marker, but also as a potential target for anticancer therapy.

Cervical cancer is a public health problem in Brazil, with annual incidence rates of 20-40 cases/100,000 women. Most patients with recurrent disease have symptoms from locoregional disease and may develop renal failure. This study aims to evaluate the outcome of patients with recurrent cervical cancer who underwent percutaneous nephrostomy (PN). We reviewed the medical records of 50 such patients who were referred to the Palliative Care Unit of the Brazilian National Cancer Institute from January 2002 to October 2006. Median age was 44 years (range, 26-67 years). Half the patients had improvement in pain or uremic symptoms, and seven (14%) had improved performance status (PS) after the procedure. Thirty patients (60%) had improvement of renal function; median creatinine levels before and after PN were 6.4 and 3.7mg/dL, respectively (P<0.05). Median overall survival after PN was 8.9 weeks (95% confidence interval [CI]: 7.4-10.3). Median survival was 9.9 weeks (95% CI: 8.7-11.0) in 40 patients with baseline PS 1-3 and one week (95% CI: 0.1-1.9) in 10 patients with PS 4 (log rank, P<0.0001). Median survival in patients with and without improvement of renal function after PN was 10.0 weeks (95% CI: 8.6-11.3) and 2.6 weeks (95% CI: 0-11.3), respectively (log rank, P=0.01). Twenty-nine patients (58%) died from renal failure. Complications were mainly urinary tract infection (n=10), catheter loss (n=9), and bleeding (n=1). These data suggest that PN can be of clinical benefit for carefully selected patients with recurrent cervical cancer.

Purpose: Lung cancer is an epidemic disease in developing countries. Incorporation of new active drugs in the neoadjuvant treatment of operable patients might lead to improved outcomes. Postchemotherapy mediastinal-based treatment decisions allow for in vivo testing of activity and could help to determine the ideal local treatment., Patients and Methods: This phase II trial enrolled patients with documented non-small-cell lung cancer, clinically staged IB-IIIA, and considered candidates for surgical resection. Patients received 3 cycles of neoadjuvant chemotherapy with alternating doublets: cisplatin/gemcitabine; gemcitabine/vinorelbine, and cisplatin/vinorelbine. After neoadjuvant treatment, clinical restaging was performed. Patients without evidence of progression underwent mediastinoscopy. Those with negative mediastinal nodes were taken to surgery whereas those with positive nodes were treated with radiation therapy., Results: Between January 2001 and August 2002, 30 patients were included. The median age was 56 years, 66% of the patients were men, 43% of the patients had adenocarcinoma, and 34% had squamous cell carcinoma. Clinical staging was IB in 9 patients (30%), IIB in 7 (23%), and IIIA in 14 (47%). Median tumor size was 6.5 cm (range, 3-11 cm). Twenty-three patients (77%) had clinical response to neoadjuvant chemotherapy. Eight of 12 patients (67%) with N2 disease had clinical downstaging. Twenty-two patients (73%) were taken to surgery. Complete resection rate was achieved in 21 patients (70%). Treatment was well tolerated., Conclusion: Localized non-small-cell lung cancer is very sensitive to chemotherapy. Postchemotherapy mediastinal-based treatment decision led to a high complete resection rate, even in patients with large tumors. This strategy deserves further investigation.

Breast cancer is the most common malignancy among women in Western countries. The management of patients with nonmetastatic breast cancer with primary endocrine therapy has evolved dramatically in the past decade. Neoadjuvant treatment has been used to turn inoperable tumors into operable tumors and also to downstage tumors. Hormone receptor-positive breast tumors exposed to neoadjuvant chemotherapy have lower rates of pathologic complete response than hormone receptor-negative tumors. Recently, clinical trials showed an increased response rate and a higher rate of breast-conserving surgery with aromatase inhibitors compared with tamoxifen. Exploratory data suggest that predictive markers of response include a higher estrogen receptor expression level and a negative HER2 status. With the introduction of "biologic" agents and surrogate markers like Ki-67, several studies are evaluating which patients are more likely to respond to preoperative hormonal agents. This review summarizes recent data on neoadjuvant endocrine therapy for breast cancer and the implication of predictive markers of response into clinical practice and future research.