Background

Some studies suggest that detection and tracking of ctDNA in early breast cancer (EBC) may predict risk of clinical recurrence, but robust prospective data are missing. We performed a systematic review and meta-analysis (MA) of studies exploring ctDNA as a biomarker for pathologic complete response (pCR) and survival outcomes in pts with EBC receiving neoadjuvant chemotherapy (NACT).

Methods

Following the PRISMA guidelines, we conducted a systematic search in Medline, Web of Science, PubMed, Cochrane and LibraryOpen Grey. Inclusion criteria was: (i) observational studies, prospective or retrospective, and randomized control trials (RCT), ii) human studies, iii) breast cancer patients undergoing neoadjuvant systemic therapy of any type, iv) documented serial serum ctDNA and outcome data such as pCR, DFS or EFS or RFS or DDFS and OS. Study quality was assessed with REMARK score and a funnel plot assessed risk of bias. The endpoints were: i) positive (PPV) and negative predict value (NPV) of ctDNA for pCR; ii) impact of ctDNA at baseline and after NACT on relapse free survival (RFS) and overall survival (OS); iii) odds ratio (OR) for pCR depending on the ctDNA at baseline and iv) subgroup analysis for impact of ctDNA post-surgery on RFS in triple-negative breast cancer (TNBC). ctDNA was treated as a binary variable for all comparisons.

Results

We identified 199 articles, 11 of which met the eligibility criteria and were included in the meta-analysis. Overall, there was no association between baseline ctDNA and pCR (OR 0.93; 95%CI 0.32 – 2.66) and the diagnostic accuracy of cDNA for pCR was low (PPV 0.24 and NPV 0.65). However, presence of ctDNA at baseline was related to worse RFS (HR 4.22, 95%CI 1.29 – 13.8) and worse OS (HR 19.1; 95%CI 6.9 – 53). Moreover, the persistence of ctDNA after NACT was predictive for worse RFS (HR 5.67; 2.73 – 11.75) and OS (HR 4; 1.9 - 8.42). In the subgroup of TNBC, presence of ctDNA after NACT and surgery was also related with worse RFS (HR 3.46; 1.93; 6.18).

Conclusions

Shredding of ctDNA at baseline and especially after NACT identifies a subset of patients with worse prognosis and may be an additional tool to select patients requiring treatment escalation or consider de-escalation.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

M. Bellet: Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: PFizer; Financial Interests, Personal, Other, Travel Expenses: Pfizer; Financial Interests, Personal, Speaker’s Bureau: Pfizer; Financial Interests, Personal, Speaker’s Bureau: Novartis; Financial Interests, Personal, Speaker’s Bureau: Lilly. E. Zamora: Financial Interests, Personal, Other, personal fees: Roche; Financial Interests, Personal, Other, personal fees: Novartis; Non-Financial Interests, Personal, Other, non-financial support: Lilly. C. Saura Manich: Financial Interests, Personal, Other, I have served as consultant, participated in advisory boards or received travel grants: AstraZeneca; Financial Interests, Personal, Other, I have served as consultant, participated in advisory boards or received travel grants: Daiichi Sankyo; Financial Interests, Personal, Other, I have served as consultant, participated in advisory boards or received travel grants: Eisai; Financial Interests, Personal, Other, I have served as consultant, participated in advisory boards or received travel grants: Exact Sciences; Financial Interests, Personal, Other, I have served as consultant, participated in advisory boards or received travel grants: Exeter Pharma; Financial Interests, Personal, Other, I have served as consultant, participated in advisory boards or received travel grants: F. Hoffmann-La Roche Ltd.; Financial Interests, Personal, Other, I have served as consultant, participated in advisory boards or received travel grants: Merck Sharp & Dohme; Financial Interests, Personal, Other, I have served as consultant, participated in advisory boards or received travel grants: Novartis; Financial Interests, Personal, Other, I have served as consultant, participated in advisory boards or received travel grants: Pfizer; Financial Interests, Personal, Other, I have served as consultant, participated in advisory boards or received travel grants: Philips; Financial Interests, Personal, Other, I have served as consultant, participated in advisory boards or received travel grants: Pierre Fabre; Financial Interests, Personal, Other, I have served as consultant, participated in advisory boards or received travel grants: Puma; Financial Interests, Personal, Other, I have served as consultant, participated in advisory boards or received travel grants: Roche; Financial Interests, Personal, Other, I have served as consultant, participated in advisory boards or received travel grants: Sanofi-Aventis; Financial Interests, Personal, Other, I have served as consultant, participated in advisory boards or received travel grants: Seagen; Financial Interests, Personal, Other, I have served as consultant, participated in advisory boards or received travel grants: Zymeworks. G. Villacampa Javierre: Financial Interests, Personal, Advisory Role, advisory/consultancy fees: AstraZeneca; Financial Interests, Personal, Expert Testimony: MSD. A.M. Antunes De Melo e Oliveira: Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Philips Healthcare; Financial Interests, Institutional, Research Grant: Genentech; Financial Interests, Institutional, Research Grant: Roche; Financial Interests, Institutional, Research Grant: Genetech; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: Immunomedics; Financial Interests, Institutional, Research Grant: Seattle Genetics; Financial Interests, Institutional, Research Grant: GSK; Financial Interests, Institutional, Research Grant: Boehringer Ingelheim; Financial Interests, Institutional, Research Grant: PUMA Biotechnology; Financial Interests, Personal, Advisory Role: Roche/Genentech; Financial Interests, Personal, Advisory Role: GSK; Financial Interests, Personal, Advisory Role: PUMA; Financial Interests, Personal, Advisory Role: Biotechnology; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Other, Honoraria: Roche; Financial Interests, Personal, Other, Honoraria: Seattle Genetics; Financial Interests, Personal, Other, Honoraria Grants: Novartis; Financial Interests, Personal, Other, Travel Grants: Roche; Financial Interests, Personal, Other, Travel Grants: Pierre-Fabre; Financial Interests, Personal, Other, Travel Grants: Novartis. All other authors have declared no conflicts of interest.

Background

Changes in prevalence and therapeutic landscapes of mCRC have translated into a progressive increase of refMCRC population. The efficacy of the available therapies in this setting is limited. Prognostic groups have been evaluated to determine better which patients (pts) could benefit from late-line treatments. We aim to explore the numeric representation of these groups in a real population that would support this strategy as a tool in daily care.

Methods

A cohort of mCRC pts treated at our hospital was retrospectively reviewed using medical charts from 2010 to 2020. Clinical, laboratory and molecular data were evaluated. We divided pts into 3 clinical groups according to previously reported prognostic characteristics: Good Prognostic Characteristics (GPC) defined as ≥18 m since metastatic disease debut, <3 metastatic sites and presence of liver metastasis, Best Prognostic Characteristics (BPC) defined as ≥18 m, since metastatic disease debut, < 3 metastatic sites and absence of liver metastases and Poor Prognostic Characteristics (PPC) defined as < 18m since metastatic disease debut and/or ≥3 metastatic sites. Statistical analysis was done using R version 4.

Results

A total of 735 out of 2365 mCRC pts (35%) were identified as refMCRC. Median age at diagnosis was 59 years, 130 pts (18%) were < 50y. Molecular profiles were: KRAS mutant (mt): 339 (46%), BRAF mt: 87 (12%) and MSI-H 29 (4%). In our cohort, 408/735 (55.51%) pts received > 3 lines of therapy (median lines 4, IQR 3-8) and 50.98% of these pts were included in clinical trials. The prognostic subgroup classification was: 266 pts (36%) GPC, 136 (19%) BPC and 333 (45%) PPC. The mOS of the cohort was 12.6m (11.4-13.9) and OS according to Prognostic Characteristics was: GPC 14.1m (11.8-16.4), BPC 16m (14.6-19.4) and PPC 10m (8.3-11.5).

Conclusions

According to data previously reported, prognostic characteristic subgroups are well represented in this cohort with a similar distribution and survival outcomes. We should further explore the potential utility of this tool in routine clinical practice or clinical trials. Of note, 35% of the pts in our series received a third-line therapy and more than a half were included in clinical trials with longer mOS compared to previous data.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

F. Salva: Financial Interests, Personal, Research Grant: Hoffman-La Roche; Sanofi Aventin; Amgen; Merck Serono; Servier; Bristol-Myers Squibb; Financial Interests, Personal, Advisory Board: Hoffman-La Roche; Sanofi Aventin; Amgen; Merck Serono; Servier; Bristol-Myers Squibb; Financial Interests, Personal, Sponsor/Funding: Hoffman-La Roche; Sanofi Aventin; Amgen; Merck Serono; Servier; Bristol-Myers Squibb; Financial Interests, Institutional, Other: Hoffman La-Roche. J. Ros: Financial Interests, Personal, Advisory Role: Sanofi; Financial Interests, Institutional, Other, Clinical trial investigator: Bristol-Myers Squibb; Financial Interests, Institutional, Advisory Role: Servier; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Sanofi. I. Baraibar: Financial Interests, Personal, Advisory Role: Sanofi; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Amgen; Sanofi; Financial Interests, Personal, Other, Honoraria: Sanofi. G. Argiles Martinez: Financial Interests, Personal, Advisory Role: Bayer; Bristol-Myers Squibb; Genentech/Roche; Roche; Servier; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Servier; Roche; Bayer; Amgen. J.L. Cuadra Urteaga: Financial Interests, Personal and Institutional, Sponsor/Funding: Amgen; Lilly. J. Capdevila: Financial Interests, Personal, Advisory Role: Novartis; Ipsen; Exelixis; Bayer; Eisai; AAA; Amgen; Sanofi; Merck; Financial Interests, Institutional, Other, Honoraria: Eisai; Novartis; Ipsen; AstraZeneca; Pfizer; AAA. D. Paez: Financial Interests, Personal, Speaker’s Bureau: Merck Serono; F. Hoffmann-La Roche Ltd; Financial Interests, Personal, Advisory Role: Amgen; Sanofi. G. Villacampa Javierre: Financial Interests, Personal, Speaker’s Bureau: Merck; Astra-Zeneca. Financial Interests, Personal, Expert Testimony: Merck; Financial Interests, Personal, Advisory Role: Astra-Zeneca; R. Dienstmann: Financial Interests, Personal, Advisory Role: Roche; Boehringer Ingelheim; Financial Interests, Personal, Speaker’s Bureau: Roche; Ipsen; Amgen; Sanofi; Libbs; Merck Sharp & Dohme; Financial Interests, Personal, Research Grant: Merck; Pierre Fabre. M.E. Elez Fernandez: Financial Interests, Personal, Advisory Role: Hoffman La - Roche; Bristol Myers Squibb; Servier; Amgen; Merck Serono; Sanofi; Bayer; Array Biopharma; Financial Interests, Personal, Research Grant: Hoffman La - Roche; Bristol Myers Squibb; Servier; Amgen; Merck Serono; Sanofi; Bayer; Array Biopharma; Financial Interests, Personal, Other, Travel grants: Hoffman La - Roche; Bristol Myers Squibb; Servier; Amgen; Merck Serono; Sanofi; Bayer; Financial Interests, Institutional, Other, Investigator contribution in clinical trials: Array Biopharma; MSD; AbbVie; Amgen; GlaxoSmithKline; AstraZeneca; Merck Sharp & Dohme Corp; Bristol Myers Squibb; Novartis; Boehringer Ingelheim; Hoffman La-Roche; Medimmune; Pierre-Fabre; Sanofi Aventis. J. Tabernero: Financial Interests, Personal, Advisory Role: Array Biopharma; AstraZeneca; Avvinity; Bayer; Boehringer Ingelheim; Chugai; Daiichi Sankyo; F. Hoffmann-La Roche Ltd; Genentech Inc; HalioDX SAS; Hutchison MediPharma International; Ikena Oncology; IQVIA; Lilly; Menarini; Merck Serono; Merus; MSD; Mirati; Neophore; Novartis; Orion Biotechnology; Peptomyc; Pfizer; Pierre Fabre; Samsung Bioepis; Sanofi; Seattle Genetics; Servier; Taiho; Tessa Therapeutics; TheraMyc; Financial Interests, Personal, Other: Imedex; Medscape Education; MJH Life Sciences; PeerView Institute for Medical Education and Physicians Education Resource (PER). All other authors have declared no conflicts of interest.

Background

BRAF-V600E mt mCRC is an aggressive disease with poor OS under standard chemotherapy. Treatment with doublet and triplet targeted combinations, such as BRAF inhibitor+ antiEGFR+/- MEK inhibitor, has been shown to improve outcomes. Prognostic factors in this population have been already described. However, prognostic factors in a homogenous population under BRAF inhibitor-based treatment have not been previously described.

Methods

A prospective international cohort of patients who received doublet or triplet anti-BRAF combinations in clinical trials or as compassionate use. Univariate Cox models for OS were constructed and the strongest predictors in stepwise variable selection were used to develop a prognostic score. The final multivariate model with selected predictors was stratified by prior lines.

Results

In total, 77 pts were enrolled. Median age 60.3 y (33-83), 55.8% female, 66.2% right-sided tumors, 60% received 2 or more prior chemotherapy lines. Three patients (4%) achieved CR and 25.7% had PR. 50 patients received doublet, and 27 patients received triplet. Overall, median PFS was 4.9m (CI95% 4.3-6.5) and median OS was 8.2 months (m) (CI95% 7.3-11.6). ECOG performance status, stage, number of tumour sites, presence of liver metastases, WBC, neutrophils, albumin CEA and NLR levels were associated with OS (p-value <0.05 in the univariate analysis). In the multivariate analysis, the most parsimonious model included four factors: ECOG, presence of liver metastases, CEA, and NLR levels. We stratified patients into three risk prognostic groups based on their number of presenting risk factors: 0 low risk (n = 17); 1-2, intermediate risk (n = 39); 3 or 4, high risk (n = 21). These three prognostic groups showed differentiated OS outcomes, with a median OS of 23.2m, 9.8m [HR=6.6, p<0.001], and 5m [HR=39.9, p<0.001] respectively.

Conclusions

Patients characteristics such as ECOG and surrogates of tumor burden like CEA levels or the number of metastatic sites remain important OS determinants for this particular population. Our study suggests that these prognostic factors could help in clinical practice and may be considered as stratification factors in future clinical trials.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

I. Baraibar: Financial Interests, Personal, Invited Speaker: Sanofi; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Amgen, Sanofi. D. Ciardiello: Financial Interests, Personal, Other, travel grant: Luigi Van Vitelli University. R.D.A. Toledo: Financial Interests, Personal, Research Grant: Novartis, AstraZeneca and Beigene. E. Martinelli: Financial Interests, Personal, Invited Speaker: AstraZeneca, Amgen, Bayer, Merck-Serono, Roche, Sanofi, Servier, Pierre-Fabre. F. Ciardiello: Financial Interests, Personal, Invited Speaker, Advisor and speaker: Roche, Amgen, Merck-Serono, Pfizer, Sanofi, Bayer, BMS, Cellgene, Lilly; Financial Interests, Institutional, Research Grant: Bayer, Roche, Merck-Serono, Amgen, AstraZeneca, Takeda. A. Vivancos: Financial Interests, Personal, Advisory Board, advisory role, travel grants, research grants: offman La - Roche, Bristol Myers Squibb, Servier, Amgen, Merck Serono, Array Biopharma, Sanofi, Bayer; Financial Interests, Institutional, Research Grant: Array Biopharma, MSD, AbbVie, Amgen, GlaxoSmithKline, AstraZeneca, Merck Sharp & Dohme Corp., Bristol Myers Squibb, Novartis, Boehringer Ingelheim, Hoffman La-Roche, Medimmune, Pierre-Fabre, Sanofi Aventis.. R. Dienstmann: Financial Interests, Personal, Advisory Board: Roche, Boehringer Ingelheim; Financial Interests, Personal, Invited Speaker: Roche, Ipsen, Amgen, Servier, Sanofi, Libbs, Merck Sharp & Dohme; Financial Interests, Personal, Research Grant: Merck and Pierre Fabre. J. Tabernero: Financial Interests, Personal, Advisory Board: array Biopharma, AstraZeneca, Avvinity, Bayer, Boehringer Ingelheim, Chugai, Diichi Sankyo, Roche, Genentech, HalioDX, Hutchinson MediPharma, Ikena Oncology, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore; Financial Interests, Institutional, Sponsor/Funding, Financial support for clinical trials or contracted research: Amgen Inc, Array Biopharma, AstraZeneca, BeiGene, Boehringer Ingelheim, BMS, Celgene, Debiopharm, Roche, Genentech Inc, Halio Dx SAS, Hutchinson MediPharma, Janssen-Cilag, MedImmune, Menarini, Merch Health KGAA, Merck Shapr and Dohme, MErus NV, Mirati, No; Non-Financial Interests, Personal and Institutional, Other: Role of Principal Investigator, Coordinating Investigator or Steering Committee member: Array Biopharma, AstraZeneca Pharmaceutical, BeiGene, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Debiopharm, F.Hoffmann-La Roche, Genentech, HalioDX, Hutchin. M.E. Elez Fernandez: Financial Interests, Personal, Invited Speaker: Hoffman La - Roche, Bristol Myers Squibb, Servier, Amgen, Merck Serono, Array Biopharma, Sanofi, Bayer, Hoffman La - Roche, Bristol Myers Squibb, Servier, Amgen, Merck Serono, Array Biopharma, Sanofi, Bayer; Financial Interests, Institutional, Research Grant: Array Biopharma, MSD, AbbVie, Amgen, GlaxoSmithKline, Astrazeneca, Merck Sharp & Dohme Corp., Bristol Myers Squibb, Novartis, Boehringer Ingelheim, Hoffman La-Roche, Medimmune, Pierre-Fabre, Sanofi Aventis. All other authors have declared no conflicts of interest.

Background

Young-onset colorectal cancer (YOCR) is defined as diagnosis below the age of 50. The incidence of YOCRC is increasing at an alarming rate, but causes and pathogenesis remain unknown and YOCRC is not well characterized. We aimed to characterize the molecular characteristics of YOCRC in patients (pts) diagnosed at our centre and to evaluate the impact of molecular tumor profiling (MTP) in ameliorating the current development in metastatic YOCR.

Methods

Pts with a diagnosis of metastatic YOCR visited for the first time at Vall d’Hebron University Hospital between January 2017 and October 2020 were included in the analysis. Data of MTP including alterations (mt) detected by VHIO-Card Amplicon panel and VHIO-Card-300-v3 panel and data concerning enrollment in phase I trials using molecular targeted agents (MTAs) were collected. Benefit was calculated comparing treatment failure of prior line (TTF1) to the MTAs’ one (TTF2). TTF2/TTF1≥1.3 supposed MTAs benefit.

Results

177 pts presented metastatic YOCR of whom 105 patients had data of MTP. MTP status was: MSI-H: 2 (6%), P53mt 83 (79%), APCmt 61 (58%), KRASmt: 53 (50%), NRASmt: 4 (4%), BRAFmt: 5 (5%), PIK3CAmt: 16 (15%), RNF43mt: 4 (4%), FBXW7mt: 3 (3%), BRCA1mt: 3 (3%), NOTCH1mt: 2 (2%), CTNNB1mt: 1 (1%), ATMmt: 1 (1%). No Her2 alterations were observed. 33 pts (18.6%) were included in phase I trials (PhIT) testing BRAF inh (1), Wnt inh (3), VEGF inh (1), anti-tubulin agents (5), MET inh (1), antiEGFR (1), immunotherapy-based treatment (IT) (18) and others (3). Median of previous lines before inclusion in PhIT: 2 (1-5). Median (m)TTF1 was 28.3 weeks (w) (1.4w-105w), mTTF2 9.7w (2.1w-234w). 6 pts (18.2%) presented a TTF2/TTF1 ratio ≥1.3, of which 5 received IT. In 5 pts (15.2%), treatment was selected based on actionable molecular alterations (RAS/BRAF wt and MSI status), 3 presenting benefit.

Conclusions

YOCR does not present particular molecular alterations in our cohort in current screening programs (SP) and do not differ from historical data in overall mCRC population, hindering enrollment in PhIT using matched MTA. Specific SP for YOCR should be developed. Significant benefit is observed for YOCR included in PhIT treated with IT and intrinsic mechanisms should be further investigated.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

I. Baraibar Argota: Financial Interests, Personal, Invited Speaker: Sanofi. J. Ros: Financial Interests, Personal, Invited Speaker: Sanofi. J. Capdevila: Financial Interests, Personal, Invited Speaker: 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 Acc. E. Garralda: Financial Interests, Other: Consulting or Advisory Role: Roche, Ellipses Pharma, Neomed Therapeutics, Janssen, Boehringer Ingelheim, Seattle Genetics, TFS, Alkermes, Thermo Fisher Scientific, Bristol-Myers Squibb; Speakers’ Bureau: MSD, Roche, Thermo Fisher Scientific Research Funding. P. Nuciforo: Financial Interests, Personal, Invited Speaker: Honoraria: Bayer, Novartis, MSD Oncology, MSD Oncology Consulting or Advisory Role: Bayer, MSD Oncology Travel, Accommodations, Expenses: Novartis. R. Dienstmann: Financial Interests, Personal, Invited Speaker: Consulting or Advisory Role: Roche Speakers’ Bureau: Roche, Ipsen, Sanofi, MSD Oncology, Servier, Amgen Research Funding: Merck. A. Vivancos: Financial Interests, Invited Speaker: Consulting or Advisory Role: Guardant Health, Novartis, Bayer Health. J. Tabernero: Financial Interests, Personal and Institutional, Other: Josep Tabernero reports personal financial interest in form of scientific consultancy role for Array Biopharma, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Chugai, Genentech, Inc., Genmab A/S, Halozyme, Imugene Limited, Inflection Biosciences Limi. M.E. Elez Fernandez: Financial Interests, Personal, Invited Speaker: Consulting or Advisory Role: Amgen, Roche, Merck Serono, Sanofi, Servier, Bayer, Pierre Fabre Research Funding: Merck Serono, Sanofi/Aventis (Inst) Travel, Accommodations, Expenses: Roche, Merck Serono, Sanofi, Amgen. All other authors have declared no conflicts of interest.

Background

The aim of (post-)/(neo)adjuvant chemotherapy and HER2-targeted therapy in HER2+ eBC is to prevent locoregional recurrences and development of distant metastases. Despite significant improvements of long-term clinical outcomes, (late) recurrences are still frequently observed with longer follow-up. Neratinib is an irreversible pan-HER tyrosine kinase inhibitor registered in Europe as extended adjuvant treatment for patients with HR-positive (HR+), HER2+ eBC who completed adjuvant trastuzumab-based therapy ≤1 year before starting neratinib (EMA-/Swissmedic-label” population). In the ExteNET study, neratinib improved the 5-year iDFS-rate by 5.1% versus placebo (90.8% vs. 85.7%; HR 0.58 [95% CI 0.41-0.82]) in this population, mainly by prolonging the time to development of distant metastases. Diarrhea, the most common grade 3 adverse event (neratinib: 39% without primary diarrhea prophylaxis, median cumulative duration 5 days; placebo: 1%; no grade 4 events) can generally be managed through adequate diarrhea prophylaxis and treatment management. ELEANOR is the first NIS to investigate real-world use of neratinib in the modern treatment landscape in the registered population in Germany, Austria and Switzerland. 200 female patients are planned to be documented in accordance with the SmPC.

Trial design

The primary objective is patients’ adherence to neratinib treatment. Secondary objectives include patient and disease characteristics, details on prior trastuzumab-based therapies (including pertuzumab and T-DM1), neratinib doses and concurrent medication, relapses, safety, and quality of life (QoL). CANKADO, an application developed to support patient/physician communication, is an integral part of the NIS. Different CANKADO modules can be used optionally, including QoL documentation (EQ-5D-5L- and diarrhea-specific questionnaires) and continuous documentation of health status and symptoms. As of 2021-05-03, 116 patients had been enrolled at 42 sites, including hospitals and practices.

Legal entity responsible for the study

Pierre Fabre Pharma GmbH Germany; Pierre Fabre Pharma Austria; Pierre Fabre Pharma AG Switzerland.

Funding

Pierre Fabre Pharma GmbH Germany, Pierre Fabre Pharma Austria, Pierre Fabre Pharma AG Switzerland.

Disclosure

N. Harbeck: Financial Interests, Personal, Advisory Role: AstraZeneca ,BMS, Celgene, Daiichi Sankyo, Genomic Health, Eli Lilly, MSD, Novartis, Odonate, Pierre Fabre, Pfizer, Roche, Sandoz/Hexal, Seattle Genetics; Financial Interests, Personal, Other, Lectures: Amgen, AstraZeneca, Daiichi Sankyo, Eli Lilly, MSD, Novartis, Pierre Fabre, Pfizer, Roche, Seattle Genetics; Financial Interests, Personal, Stocks/Shares, West German Study Group - minority ownership academic study group: WSG; Financial Interests, Institutional, Invited Speaker, all directly to my institution (clinical phase II-IV trials): several sponsors; Financial Interests, Institutional, Sponsor/Funding, clinical phase II-IV trials: several sponsors; Non-Financial Interests, Personal, Leadership Role: AGO breast commission. D. Lüftner: Non-Financial Interests, Personal, Invited Speaker: Amgen, Pierre Fabre, Pfizer, Eli Lilly; Non-Financial Interests, Institutional, Writing Engagements: Pierre Fabre, Novartis, Eli Lilly; Non-Financial Interests, Personal, Speaker’s Bureau: GSK, Loreal, Teva, Amgen, Pfizer, Novartis; Non-Financial Interests, Personal, Advisory Board: Gilead, Sanofi Aventis, Daiichi Sankyo; Non-Financial Interests, Institutional, Research Grant: Novartis; Non-Financial Interests, Institutional, Project Lead: Pierre Fabre; Non-Financial Interests, Personal, Principal Investigator: Pierre Fabre; Non-Financial Interests, Personal, Principal Investigator: Daiichi Sankyo; Non-Financial Interests, Personal, Principal Investigator: Samsung. U. Breitenstein: Financial Interests, Institutional, Invited Speaker: Novartis, Roche, AstraZeneca, Eli Lilly; Financial Interests, Institutional, Advisory Board: Novartis, Roche, AstraZeneca, Eli Lilly; Financial Interests, Institutional, Principal Investigator: Roche, Eli Lilly, Pierre Fabre, Novartis, Pfizer, AstraZeneca, SAKK; Financial Interests, Institutional, Member: SGMO, SGS, SAKK. C. Jackisch: Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca, Eisai, Pfizer, Eli Lilly, Novartis, Exact Sciences, AstraZeneca; Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, Eli Lilly, Exact Sciences, Novartis, Pfizer; Non-Financial Interests, Personal, Principal Investigator: Roche. V. Müller: Financial Interests, Personal, Invited Speaker: Amgen, AstraZeneca, Daiichi Sankyo, Eisai, Pfizer, MSD, Novartis, Roche, Teva, Seattle Genetics; Financial Interests, Personal, Advisory Role: Genomic Health, Hexal, Roche, Pierre Fabre, Amgen, ClinSol, Novartis, MSD, Daiichi Sankyo, Eisai, Eli Lilly, Tesaro, Nektar; Financial Interests, Institutional, Other, research support: Novartis, Roche, Seattle Genetics Genentech. M. Schmidt: Financial Interests, Institutional, Research Grant: Pierre Fabre, Roche, Pfizer, Novartis, AstraZeneca, Eisai, Pantarhei, BioNTech, Genentech; Financial Interests, Personal, Advisory Role: Pierre Fabre, Roche, Pfizer, Novartis, AstraZeneca, Eisai, Amgen, Pantarhei, BioNTech, SeaGen; Non-Financial Interests, Personal, Other: Roche, Pfizer, Pantarhei, BioNTech; Non-Financial Interests, Personal, Other, Issued patent EP: 2951317, Issued patent EP: 2390370: Patent. M. Balic: Financial Interests, Personal, Invited Speaker: Amgen, AstraZeneca, Eli Lilly, Novartis, MSD, Pierre Fabre, Pfizer, Roche; Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Daiichi Sankyo, Bayer, Eli Lilly, MSD, Novartis, Pfizer, Roche, Samsung, Seagen; Financial Interests, Institutional, Research Grant: Novartis, Eli Lilly, Pfizer, Celgene; Financial Interests, Personal, Funding, Travel/ Accomodation/Expenses: AstraZeneca, Amgen, Bayer, Celgene, Eli Lilly, MSD, Novartis, Pierre Fabre, Roche; Financial Interests, Institutional, Principal Investigator: ABCSG, IBCSG, BIG, AstraZeneca, MSD, Eli Lilly, Roche. G. Rinnerthaler: Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Novartis, BMS, Roche, Pfizer, Eli Lilly; Financial Interests, Personal, Advisory Board: Pierre Fabre, MSD, Roche, Novartis, Pfizer, Eli Lilly, Daiichi Sankyo; Financial Interests, Institutional, Funding: Roche. M. Schwitter: Non-Financial Interests, Personal and Institutional, Advisory Board: Pierre Fabre. K. Zaman: Financial Interests, Institutional, Advisory Role: Eli Lilly, Novartis, Roche, SMD Oncology, Mylan, Daiichi Sankyo, Pierre Fabre; Financial Interests, Institutional, Research Grant: Roche/Genentech; Financial Interests, Personal, Other, Travel/ Accomodation/Expenses: Roche; Financial Interests, Institutional, Other, Travel/ Accomodation/Expenses: Pierre Fabre, MSD Oncology, Pierre Fabre. D. Wrobel: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Other: Novartis. M. Zaiss: Financial Interests, Personal, Invited Speaker: AstraZeneca, RG, AKS, Vifor; Financial Interests, Personal, Advisory Board: AstraZeneca, Roche, Pfizer, Janssen, Novartis, AbbVie, Eli Lilly; Financial Interests, Institutional, Principal Investigator: GBG, Eli Lilly, Roche. T. Schinköthe: Financial Interests, Personal, Full or part-time Employment: Cancado; Financial Interests, Personal, Ownership Interest: Cancado. R. Bartsch: Financial Interests, Personal, Invited Speaker: AstraZeneca, Daiichi Sankyo, Eli Lilly, MSD, Novartis, Pfizer, Pierre Fabre, Roche, Seagen; Financial Interests, Personal, Advisory Board: AstraZeneca, Daiichi Sankyo, Eisai, Eli Lilly, MSD, Novartis, Pfizer, Pierre Fabre, PUMA, Roche, Seagen; Financial Interests, Institutional, Research Grant: Daiichi Sankyo, MSD; Non-Financial Interests, Institutional, Research Grant: Daiichi Sankyo, MSD; Financial Interests, Institutional, Principal Investigator: ABCSG, Daiichi Sankyo, Eli Lilly, Novartis, Roche; Non-Financial Interests, Personal, Member: ESMO, österreichische Gesellschaft für Senologie, österr. Gesellschaft für Hämatologie und Onkologie. All other authors have declared no conflicts of interest.

Background

The aim of this study was to assess early outcomes and safety of hypofractionated radiotherapy in non-metastatic locally advanced stage T4 breast cancer.

Methods

Fifty patients irradiated between 2017 and 2020 for non-metastatic locally advanced stage T4 breast cancer (BC) were retrospectively evaluated. All patients underwent 3D conformal hypofractionated radiotherapy: 40 Gy delivered in 15 daily fractions of 2.67 Gy +/- additional boost of 13.35 Gy. Disease free survival, metastasis free survival, acute and late radiation induced toxicity were evaluated.

Results

The mean age at diagnosis was 53 (33-77) years. Thirteen (26%) patients had inflammatory BC and 37 had stage T4b BC. All patients underwent chemotherapy which was neo-adjuvant in 76% of cases. Mastectomy was performed for 96% of patients, whereas two patients had conservative surgery. Regional lymph nodes irradiation was performed for 47 (94%) of patients. Additional boost to the thoracic wall/tumor bed was delivered in 40% of cases. Eighty percent of patients experienced acute skin toxicity with 66% of grade 1 radiation dermatitis and 14% of grade 2 radiation dermatitis. No grade 3-4 radiation dermatitis was reported. Sixteen patients reported dysphagia which was well managed with non-steroidal anti-inflammatory drugs. The median follow-up was 20 (2-40) months. Late skin toxicity was observed in 48% of patients with 36% of skin colour change and 12% of radiation induced fibrosis. Twenty-six (52%) did not report any late cutaneous toxicity. Local recurrence was observed in 4 women. The mean time to local failure was 13 months. Nine patients (18%) had distant metastatic failure. Disease free survival at 36 months was 87.8% whereas metastasis free survival was 82.8%.

Conclusions

Early outcomes of hypofractionated radiotherapy for stage T4 breast cancer seemed comparable to those reported in the literature in conventional breast cancer radiotherapy. Considering the important socio-economic impact, this may encourage its use in low middle-income countries. Nonetheless, safety and efficacy of hypofractionated radiotherapy in locally advanced breast cancer need to be further studied in larger cohorts.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

The PRIMA/ENGOT-OV26/GOG-3012 (NCT02655016) phase III trial showed niraparib significantly prolongs median PFS vs placebo in patients with advanced OC responsive to 1L platinum (Pt)-based chemotherapy (CT), regardless of biomarker status. This post hoc analysis of PRIMA examined the QA-TWiST and QA-PFS of patients on maintenance niraparib vs placebo.

Methods

Patients with OC responsive to 1L Pt CT were randomised 2:1 to receive once-daily maintenance niraparib or placebo. QA-TWiST analyses were performed, defining TOX as the mean duration in which a patient experienced grade ≥2 adverse events (fatigue or asthenia, nausea, vomiting, abdominal pain, and abdominal bloating) from randomisation to disease progression/censoring. Mean QA-TWiST was calculated as U_TOX x TOX + U_TWiST x TWiST, where U_TWiST and U_TOX represent utilities applied to the time spent in TWiST and TOX health states, respectively. U_TWiST was considered 1.00, i.e., the best possible quality of life for a patient. U_TOX was calculated using EQ-5D index scores from the PRIMA trial. Restricted mean QA-PFS was calculated from the area under the quality-survival product function up to the last PFS of patients randomised to niraparib.

Results

Patient follow-up was 27.8 months. There were significant improvements in mean QA-TWiST for niraparib vs placebo in the intention-to-treat (ITT) and homologous recombination-deficient (HRd) cohorts, with mean gains of 3.5 and 5.9 months, respectively (Table). Similarly, QA-PFS was significantly longer with niraparib vs placebo in these cohorts.

Conclusions

In patients with OC, 1L niraparib maintenance was associated with significant gains in QA-TWiST and QA-PFS vs placebo, confirming the benefit of niraparib in the overall ITT population and HRd cohorts. Table: 738P

Mean QA-TWiST and QA-PFS in ITT and HRd cohorts

Clinical trial identification

NCT02655016.

Editorial acknowledgement

Medical writing support was provided by Nadia Hashash of Core Medica, London, UK, funded by GlaxoSmithKline.

Legal entity responsible for the study

GlaxoSmithKline.

Funding

GlaxoSmithKline (ID: 214211).

Disclosure

M. Barretina-Ginesta: Financial Interests, Personal, Advisory Board: Tesaro; Financial Interests, Personal, Advisory Board: GlaxoSmithKline; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Clovis Oncology; Financial Interests, Personal, Advisory Board: Pharma Mar; Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Other, Lecture fees and travel support: Tesaro; Financial Interests, Personal, Other, Lecture fees and travel support: GlaxoSmithKline; Financial Interests, Personal, Other, Lecture fees and travel support: AstraZeneca; Financial Interests, Personal, Other, Lecture fees and travel support: Roche; Financial Interests, Personal, Other, Lecture fees and travel support: Clovis Oncology; Financial Interests, Personal, Other, Lecture fees and travel support: Pharma Mar; Financial Interests, Personal, Other, Lecture fees and travel support: Merck. B.J. Monk: Financial Interests, Personal, Other, Lecture fees: Tesaro; Financial Interests, Personal, Other, Honoraria: Tesaro. B. Pothuri: Financial Interests, Personal, Research Grant: Tesaro/GSK; Financial Interests, Personal, Research Grant: AstraZeneca; Financial Interests, Personal, Research Grant: Merck; Financial Interests, Personal, Research Grant: Genentech/Roche; Financial Interests, Personal, Research Grant: Celsion; Financial Interests, Personal, Research Grant: Mersana; Financial Interests, Personal, Research Grant: Clovis Oncology; Financial Interests, Personal, Advisory Board: Tesaro/GSK; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Advisory Board: Toray; Financial Interests, Personal, Advisory Board: Mersana; Financial Interests, Personal, Advisory Board: Elevar; Financial Interests, Personal, Advisory Board: Arquer; Financial Interests, Personal, Advisory Board: Eisai. D. Chase: Financial Interests, Personal, Other, Personal Fees: GlaxoSmithKline; Financial Interests, Personal, Other, Honoraria: Roche; Financial Interests, Personal, Other, Consultancy fees: Mateon Therapeutics; Financial Interests, Personal, Other, Consultancy fees: AstraZeneca; Financial Interests, Personal, Research Grant: Genentech. D. Lorusso: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Clovis Oncology; Financial Interests, Personal, Advisory Board: Genmab; Financial Interests, Personal, Advisory Board: Immunogen; Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Personal, Research Grant: Pharma Mar; Financial Interests, Personal, Other, Consulting Fees: Pharma Mar; Financial Interests, Personal, Research Grant: Merck; Financial Interests, Personal, Advisory Board: Merck. A. Redondo: Financial Interests, Personal, Research Grant: Pharma Mar ; Financial Interests, Personal, Advisory Role: Pharma Mar; Financial Interests, Personal, Research Grant: Roche; Financial Interests, Personal, Advisory Role: Roche; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role: Tesaro; Financial Interests, Personal, Research Grant: Eisai. R. Shah: Financial Interests, Personal, Full or part-time Employment: Open Health Evidence and Access. N. Kebede: Financial Interests, Personal, Full or part-time Employment: Open Health Evidence and Access. C. Hawkes: Financial Interests, Personal, Full or part-time Employment: GlaxoSmithKline. D. Gupta: Financial Interests, Personal, Full or part-time Employment: GlaxoSmithKline. T. Woodward: Financial Interests, Personal, Full or part-time Employment: GlaxoSmithKline. D.M. O'Malley: Financial Interests, Personal, Research Grant: Clovis; Financial Interests, Personal, Other, Personal fees: Clovis; Financial Interests, Personal, Advisory Board: Agenus; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Advisory Board: Genentech/Roche; Financial Interests, Personal, Advisory Board: Immunogen; Financial Interests, Personal, Advisory Board: Iovance Biotherapeutics; Financial Interests, Personal, Advisory Board: Janssen/Johnson & Johnson; Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Advisory Board: Mersana; Financial Interests, Personal, Advisory Board: Myriad; Financial Interests, Personal, Advisory Board: Novartis Pharmaceuticals; Financial Interests, Personal, Advisory Board: Novocure; Financial Interests, Personal, Advisory Board: Regeneron Pharmaceuticals; Financial Interests, Personal, Advisory Board: SeaGen; Financial Interests, Personal, Advisory Board: Tarveda; Financial Interests, Personal, Advisory Board: Tesaro/GSK; Financial Interests, Personal, Other, Steering committee: Amgen; Financial Interests, Personal, Other, Consultant: AbbVie; Financial Interests, Personal, Other, Consultant: Agenus; Financial Interests, Personal, Other, Consultant: Ambry; Financial Interests, Personal, Other, Consultant: AstraZeneca; Financial Interests, Personal, Other, Consultant: Eisai; Financial Interests, Personal, Other, Consultant: Genentech/Roche; Financial Interests, Personal, Invited Speaker, Consultant: GOG Foundation; Financial Interests, Personal, Invited Speaker, Consultant: Immunogen; Financial Interests, Personal, Invited Speaker, Consultant: Iovance Biotherapeutics; Financial Interests, Personal, Invited Speaker, Consultant: Merck; Financial Interests, Personal, Invited Speaker, Consultant: Mersana; Financial Interests, Personal, Invited Speaker, Consultant: Novartis Pharmaceuticals; Financial Interests, Personal, Invited Speaker, Consultant: Novocure; Financial Interests, Personal, Invited Speaker, Consultant: Seagen; Financial Interests, Personal, Invited Speaker, Consultant: Tesaro/GSK; Financial Interests, Institutional, Research Grant: AbbVie; Financial Interests, Institutional, Research Grant: Agenus; Financial Interests, Institutional, Research Grant: Ajinomoto; Financial Interests, Institutional, Research Grant: Amgen; Financial Interests, Institutional, Research Grant: Array BioPharma; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Bristol-Myers Squibb; Financial Interests, Institutional, Research Grant: Cerulean Pharma; Financial Interests, Institutional, Research Grant: Eisai; Financial Interests, Institutional, Research Grant: EMD Serono; Financial Interests, Institutional, Research Grant: Ergomed Clinical Research; Financial Interests, Institutional, Research Grant: Genmab; Financial Interests, Institutional, Research Grant: Genentech/Roche; Financial Interests, Institutional, Research Grant: GOG Foundation; Financial Interests, Institutional, Research Grant: ImmunoGen; Financial Interests, Institutional, Research Grant: INC Research; Financial Interests, Institutional, Research Grant: inVentiv Health Clinical; Financial Interests, Institutional, Research Grant: Iovance Biotherapeutics; Financial Interests, Institutional, Research Grant: Janssen/Johnson & Johnson; Financial Interests, Institutional, Research Grant: Ludwig Institute for Cancer Research; Financial Interests, Institutional, Research Grant: Merck; Financial Interests, Institutional, Research Grant: Mersana; Financial Interests, Institutional, Research Grant: New Mexico Cancer Care Alliance; Financial Interests, Institutional, Research Grant: Novocure; Financial Interests, Institutional, Research Grant: PRA International; Financial Interests, Institutional, Research Grant: Regeneron Pharmaceuticals; Financial Interests, Institutional, Research Grant: Seagen; Financial Interests, Institutional, Research Grant: Serono; Financial Interests, Institutional, Research Grant: Stemcentrx; Financial Interests, Institutional, Research Grant: Tesaro/GSK; Financial Interests, Institutional, Research Grant: TRACON Pharmaceuticals; Financial Interests, Institutional, Research Grant: VentiRx; Financial Interests, Institutional, Research Grant: Yale University. A.J. Gonzalez Martin: Financial Interests, Personal, Other, Consultning fees, lecture fees, travel support: AstraZeneca; Financial Interests, Personal, Other, Consultning fees, lecture fees, travel support: Pharma Mar; Financial Interests, Personal, Other, Grant support, consulting fees, lecture fees, and travel support: Tesaro; Financial Interests, Personal, Other, Grant support, consulting fees, lecture fees, and travel support: Roche Holding; Financial Interests, Personal, Other, Consulting fees: Clovis Oncology; Financial Interests, Personal, Other, Consulting fees: Merck; Financial Interests, Personal, Other, Consulting fees: Genmab; Financial Interests, Personal, Other, Consulting fees: InnunoGen; Financial Interests, Personal, Other, Consulting fees: Oncoinvent. All other authors have declared no conflicts of interest.

Background

Pembro (programmed death protein 1 [PD-1] inhibitor) ± platinum (Pt)-based chemotherapy (CT), with pembro maintained until progression, is a standard 1L treatment for advanced/metastatic NSCLC. However, durable long-term benefit is limited to a small subset of patients. Nira, a poly(ADP-ribose) polymerase inhibitor (PARPi), promotes PARP trapping, activates the STING pathway, recruits T cells, and upregulates PD-L1, making it a promising partner for PD-1 inhibitors. Nira crosses the blood–brain barrier in animal models with 34-fold higher brain tissue exposure than other PARPi, suggesting it may reduce risk/progression of brain metastasis (BM). Nira + pembro has shown antitumour activity and acceptable safety in triple-negative breast cancer and Pt-resistant ovarian cancer (TOPACIO/KEYNOTE-162), and as 1L therapy in advanced/metastatic NSCLC (JASPER).

Trial design

ZEAL-1L (NCT04475939) is a phase III, randomised, double-blind trial comparing efficacy and safety of 1L maintenance therapy with oral nira (200/300 mg/day) + intravenous pembro (200 mg on Day 1 of each 21-day cycle; maximum 35 cycles from start of 1L induction CT) versus placebo + pembro in adults with histologically/cytologically confirmed Stage IIIB–IV NSCLC without known driver mutations and with stable disease or partial/complete response to 4–6 cycles of 1L Pt-based induction CT + pembro. Patients with asymptomatic BM (i.e. off corticosteroids and anticonvulsants for ≥7 days) are permitted. Approximately 650 patients will be randomised (1:1), with stratification by histology, PD-L1 status and response to 1L induction CT + pembro. Treatment will continue until disease progression (PD), unacceptable toxicity, death, or loss to follow-up. Imaging occurs every 6 weeks (Q6W) for 48 weeks/until PD, and Q12W for patients still on treatment thereafter. Primary endpoints are PFS and OS. Time to central nervous system progression is a key secondary endpoint; others include investigator-assessed PFS, PFS and OS by PD-L1 status, quality of life, safety and pharmacokinetics. Exploratory analyses are also planned. Enrolment began November 2020.

Clinical trial identification

NCT04475939.

Editorial acknowledgement

Medical writing support was provided by Nadia Hashash, PhD, of Core Medica, London, UK, funded by GlaxoSmithKline.

Legal entity responsible for the study

GlaxoSmithKline.

Funding

GlaxoSmithKline (ID: 213400).

Disclosure

S.S. Ramalingam: Financial Interests, Personal, Other, Consultancy fees: Amgen; Financial Interests, Personal, Other, Consultancy fees: AbbVie; Financial Interests, Personal, Other, Consultancy fees: AstraZeneca; Financial Interests, Personal, Other, Consultancy fees: Bristol Myers Squibb; Financial Interests, Personal, Other, Consultancy fees: Genentech/F. Hoffmann-La Roche; Financial Interests, Personal, Other, Consultancy fees: Merck; Financial Interests, Personal, Research Grant: Amgen; Financial Interests, Personal, Research Grant: Advaxis; Financial Interests, Personal, Research Grant: AstraZeneca; Financial Interests, Personal, Research Grant: Bristol Myers Squibb; Financial Interests, Personal, Research Grant: Merck; Financial Interests, Personal, Research Grant: Takeda; Financial Interests, Personal, Research Grant: Tesaro (a GlaxoSmithKline company). G. de Castro Jr.: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Personal, Advisory Board: Bristol Myers Squibb; Financial Interests, Personal, Advisory Board: Boehringer Ingelheim; Financial Interests, Personal, Advisory Board: Janssen; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Advisory Board: Merck Serono; Financial Interests, Personal, Advisory Board: Merck Sharp & Dohme; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Teva; Financial Interests, Personal, Advisory Board: Yuhan; Financial Interests, Personal, Other, Consultancy fees or personal fees: AstraZeneca; Financial Interests, Personal, Other, Consultancy fees or personal fees: Bayer; Financial Interests, Personal, Other, Consultancy fees or personal fees: Bristol Myers Squibb; Financial Interests, Personal, Other, Consultancy fees or personal fees: Boehringer Ingelheim; Financial Interests, Personal, Other, Consultancy fees or personal fees: Janssen; Financial Interests, Personal, Other, Consultancy fees or personal fees: Lilly; Financial Interests, Personal, Other, Consultancy fees or personal fees: Merck Serono; Financial Interests, Personal, Other, Consultancy fees or personal fees: Merck Sharp & Dohme; Financial Interests, Personal, Other, Consultancy fees or personal fees: Novartis; Financial Interests, Personal, Other, Consultancy fees or personal fees: Pfizer; Financial Interests, Personal, Other, Consultancy fees or personal fees: Roche; Financial Interests, Personal, Other, Consultancy fees or personal fees: Teva; Financial Interests, Personal, Other, Consultancy fees or personal fees: Yuhan. M.C.C. Garassino: Financial Interests, Personal, Other, Speakers’ Honoraria, Consultancy, and Advisory fees: Amgen; Financial Interests, Personal, Other, Speakers’ Honoraria, Consultancy, and Advisory fees: AstraZeneca/MedImmune; Financial Interests, Personal, Other, Speakers’ Honoraria, Consultancy, and Advisory fees: Bayer Healthcare Pharmaceuticals; Financial Interests, Personal, Other, Speakers’ Honoraria, Consultancy, and Advisory fees: Blueprint Medicines; Financial Interests, Personal, Other, Speakers’ Honoraria, Consultancy, and Advisory fees: Bristol Myers Squibb; Financial Interests, Personal, Other, Speakers’ Honoraria, Consultancy, and Advisory fees: Celgene; Financial Interests, Personal, Other, Speakers’ Honoraria, Consultancy, and Advisory fees: Daiichi Sankyo; Financial Interests, Personal, Other, Speakers’ Honoraria, Consultancy, and Advisory fees: Eli Lilly; Financial Interests, Personal, Other, Speakers’ Honoraria, Consultancy, and Advisory fees: Exelixis; Financial Interests, Personal, Other, Speakers’ Honoraria, Consultancy, and Advisory fees: GlaxoSmithKline; Financial Interests, Personal, Other, Speakers’ Honoraria, Consultancy, and Advisory fees: Incyte; Financial Interests, Personal, Other, Speakers’ Honoraria, Consultancy, and Advisory fees: Inivata; Financial Interests, Personal, Other, Speakers’ Honoraria, Consultancy, and Advisory fees: Ipsen; Financial Interests, Personal, Other, Speakers’ Honoraria, Consultancy, and Advisory fees: Janssen; Financial Interests, Personal, Other, Speakers’ Honoraria, Consultancy, and Advisory fees: MedImmune; Financial Interests, Personal, Other, Speakers’ Honoraria, Consultancy, and Advisory fees: Merck Sharp & Dohme; Financial Interests, Personal, Other, Speakers’ Honoraria, Consultancy, and Advisory fees: MSD Oncology; Financial Interests, Personal, Other, Speakers’ Honoraria, Consultancy, and Advisory fees: Novartis; Financial Interests, Personal, Other, Speakers’ Honoraria, Consultancy, and Advisory fees: Otsuka; Financial Interests, Personal, Other, Speakers’ Honoraria, Consultancy, and Advisory fees: Pfizer; Financial Interests, Personal, Other, Speakers’ Honoraria, Consultancy, and Advisory fees: Regeneron; Financial Interests, Personal, Other, Speakers’ Honoraria, Consultancy, and Advisory fees: Roche/Genentech; Financial Interests, Personal, Other, Speakers’ Honoraria, Consultancy, and Advisory fees: Sanofi-Aventis; Financial Interests, Personal, Other, Speakers’ Honoraria, Consultancy, and Advisory fees: Seattle Genetics; Financial Interests, Personal, Other, Speakers’ Honoraria, Consultancy, and Advisory fees: Spectrum Pharmaceuticals; Financial Interests, Personal, Other, Speakers’ Honoraria, Consultancy, and Advisory fees: Tiziana Life Sciences; Financial Interests, Personal, Other, Speakers’ Honoraria, Consultancy, and Advisory fees: Takeda. J. Mazieres: Financial Interests, Personal, Research Grant, Honoraria: Amgen; Financial Interests, Personal, Research Grant, Honoraria: AstraZeneca; Financial Interests, Personal, Research Grant, Honoraria: Blueprint Medicines; Financial Interests, Personal, Research Grant, Honoraria: Bristol Myers Squibb; Financial Interests, Personal, Research Grant, Honoraria: Daiichi Sankyo; Financial Interests, Personal, Research Grant, Honoraria: Hengrui; Financial Interests, Personal, Research Grant, Honoraria: Merck Sharp & Dohme; Financial Interests, Personal, Research Grant, Honoraria: Novartis; Financial Interests, Personal, Research Grant, Honoraria: Pierre Fabre; Financial Interests, Personal, Research Grant, Honoraria: Roche; Financial Interests, Personal, Research Grant: Takeda. R.E. Sanborn: Financial Interests, Personal, Research Grant, Honoraria, Research support: Amgen; Financial Interests, Personal, Research Grant, Honoraria, Research support: AstraZeneca; Financial Interests, Personal, Research Grant, Honoraria, Research support: Blueprint Medicines; Financial Interests, Personal, Research Grant, Honoraria, Research support: Bristol Myers Squibb; Financial Interests, Personal, Research Grant, Honoraria, Research support: Daiichi Sankyo; Financial Interests, Personal, Research Grant, Honoraria, Research support: Lilly; Financial Interests, Personal, Research Grant, Honoraria, Research support: EMD Serono; Financial Interests, Personal, Research Grant, Honoraria, Research support: Janssen Oncology; Financial Interests, Personal, Research Grant, Honoraria, Research support: MedImmune; Financial Interests, Personal, Research Grant, Honoraria, Research support: Merck; Financial Interests, Personal, Research Grant, Honoraria, Research support: Roche/Genentech; Financial Interests, Personal, Advisory Role, Consulting/Advisory Role fees: Amgen; Financial Interests, Personal, Advisory Role, Consulting/advisory role fees: Amgen; Financial Interests, Personal, Advisory Role, Consulting/Advisory Role fees: Blueprint Medicines; Financial Interests, Personal, Advisory Role, Consulting/Advisory Role fees: Bristol Myers Squibb; Financial Interests, Personal, Advisory Role, Consulting/Advisory Role fees: Daiichi Sankyo; Financial Interests, Personal, Advisory Role, Consulting/Advisory Role fees: Lilly; Financial Interests, Personal, Advisory Role, Consulting/Advisory Role fees: EMD Serono; Financial Interests, Personal, Advisory Role, Consulting/Advisory Role fees: Janssen Oncology; Financial Interests, Personal, Advisory Role, Consulting/Advisory Role fees: MedImmune; Financial Interests, Personal, Advisory Role, Consulting/Advisory Role fees: Merck; Financial Interests, Personal, Advisory Role, Consulting/Advisory Role fees: Roche/Genentech. E.F.F. Smit: Financial Interests, Personal, Sponsor/Funding, Research funding: AstraZeneca; Financial Interests, Personal, Sponsor/Funding, Research funding: Bayer; Financial Interests, Personal, Sponsor/Funding, Research funding: Daiichi Sankyo; Financial Interests, Personal, Sponsor/Funding, Research funding: Lilly; Financial Interests, Personal, Sponsor/Funding, Research funding: Boehringer Ingelheim; Financial Interests, Personal, Sponsor/Funding, Research funding: Bristol Myers Squibb; Financial Interests, Personal, Sponsor/Funding, Research funding: Merck KGaA; Financial Interests, Personal, Sponsor/Funding, Research funding: MSD Oncology; Financial Interests, Personal, Sponsor/Funding, Research funding: Novartis; Financial Interests, Personal, Sponsor/Funding, Research funding: Roche/Genentech; Financial Interests, Personal, Sponsor/Funding, Research funding: Seattle Genetics; Financial Interests, Personal, Sponsor/Funding, Research funding: Takeda; Financial Interests, Personal, Advisory Role, Consulting/Advisory Role fees: AstraZeneca; Financial Interests, Personal, Advisory Role, Consulting/Advisory Role fees: Bayer; Financial Interests, Personal, Advisory Role, Consulting/Advisory Role fees: Daiichi Sankyo; Financial Interests, Personal, Advisory Role, Consulting/Advisory Role fees: Lilly; Financial Interests, Personal, Advisory Role, Consulting/Advisory Role fees: Boehringer Ingelheim; Financial Interests, Personal, Advisory Role, Consulting/Advisory Role fees: Bristol Myers Squibb; Financial Interests, Personal, Advisory Role, Consulting/Advisory Role fees: Merck KGaA; Financial Interests, Personal, Advisory Role, Consulting/Advisory Role fees: MSD Oncology; Financial Interests, Personal, Advisory Role, Consulting/Advisory Role fees: Novartis; Financial Interests, Personal, Advisory Role, Consulting/Advisory Role fees: Roche/Genentech; Financial Interests, Personal, Advisory Role, Consulting/Advisory Role fees: Seattle Genetics; Financial Interests, Personal, Advisory Role, Consulting/Advisory Role fees: Takeda. D.R. Spigel: Financial Interests, Personal, Other, Consulting, Advisory Role, Research Funding and Travel fees: Aeglea Biotherapeutics; Financial Interests, Personal, Other, Consulting, Advisory Role, Research Funding and Travel fees: Agios; Financial Interests, Personal, Other, Consulting, Advisory Role, Research Funding and Travel fees: Amgen; Financial Interests, Personal, Other, Consulting, Advisory Role, Research Funding and Travel fees: Apitude Health; Financial Interests, Personal, Other, Consulting, Advisory Role, Research Funding and Travel fees: Apollomics; Financial Interests, Personal, Other, Consulting, Advisory Role, Research Funding and Travel fees: Astellas Pharma; Financial Interests, Personal, Other, Consulting, Advisory Role, Research Funding and Travel fees: AstraZeneca; Financial Interests, Personal, Other, Consulting, Advisory Role, Research Funding and Travel fees: Bayer; Financial Interests, Personal, Other, Consulting, Advisory Role, Research Funding and Travel fees: BIND Therapeutics; Financial Interests, Personal, Other, Consulting, Advisory Role, Research Funding and Travel fees: Bristol Myers Squibb; Financial Interests, Personal, Other, Consulting, Advisory Role, Research Funding and Travel fees: Calithera Biosciences; Financial Interests, Personal, Other, Consulting, Advisory Role, Research Funding and Travel fees: Celgene; Financial Interests, Personal, Other, Consulting, Advisory Role, Research Funding and Travel fees: Celldex; Financial Interests, Personal, Other, Consulting, Advisory Role, Research Funding and Travel fees: Clovis Oncology; Financial Interests, Personal, Other, Consulting, Advisory Role, Research Funding and Travel fees: Curio Science; Financial Interests, Personal, Other, Consulting, Advisory Role, Research Funding and Travel fees: Cyteir; Financial Interests, Personal, Other, Consulting, Advisory Role, Research Funding and Travel fees: Daiichi Sankyo; Financial Interests, Personal, Other, Consulting, Advisory Role, Research Funding and Travel fees: Dracen; Financial Interests, Personal, Other, Consulting, Advisory Role, Research Funding and Travel fees: Eisai; Financial Interests, Personal, Other, Consulting, Advisory Role, Research Funding and Travel fees: Elevation Oncology; Financial Interests, Personal, Other, Consulting, Advisory Role, Research Funding and Travel fees: EMD Serono; Financial Interests, Personal, Other, Consulting, Advisory Role, Research Funding and Travel fees: Evelo Therapeutics; Financial Interests, Personal, Other, Consulting, Advisory Role, Research Funding and Travel fees: Exelixis; Financial Interests, Personal, Other, Consulting, Advisory Role, Research Funding and Travel fees: Genentech/Roche; Financial Interests, Personal, Other, Consulting, Advisory Role, Research Funding and Travel fees: GlaxoSmithKline; Financial Interests, Personal, Other, Consulting, Advisory Role, Research Funding and Travel fees: GRAIL; Financial Interests, Personal, Other, Consulting, Advisory Role, Research Funding and Travel fees: G1 Therapeutics; Financial Interests, Personal, Other, Consulting, Advisory Role, Research Funding and Travel fees: Iksuda Therapeutics; Financial Interests, Personal, Other, Consulting, Advisory Role, Research Funding and Travel fees: Illumina; Financial Interests, Personal, Other, Consulting, Advisory Role, Research Funding and Travel fees: ImClone Systems; Financial Interests, Personal, Other, Consulting, Advisory Role, Research Funding and Travel fees: Immunogen; Financial Interests, Personal, Other, Consulting, Advisory Role, Research Funding and Travel fees: Intellisphere; Financial Interests, Personal, Other, Consulting, Advisory Role, Research Funding and Travel fees: Ipsen; Financial Interests, Personal, Other, Consulting, Advisory Role, Research Funding and Travel fees: Janssen Oncology; Financial Interests, Personal, Other, Consulting, Advisory Role, Research Funding and Travel fees: Jazz Pharmaceuticals; Financial Interests, Personal, Other, Consulting, Advisory Role, Research Funding and Travel fees: Lilly; Financial Interests, Personal, Other, Consulting, Advisory Role, Research Funding and Travel fees: MedImmune; Financial Interests, Personal, Other, Consulting, Advisory Role, Research Funding and Travel fees: Merck; Financial Interests, Personal, Other, Consulting, Advisory Role, Research Funding and Travel fees: Molecular Partners; Financial Interests, Personal, Other, Consulting, Advisory Role, Research Funding and Travel fees: Molecular Templates; Financial Interests, Personal, Other, Consulting, Advisory Role, Research Funding and Travel fees: Mirati Therapeutics; Financial Interests, Personal, Other, Consulting, Advisory Role, Research Funding and Travel fees: Nektar; Financial Interests, Personal, Other, Consulting, Advisory Role, Research Funding and Travel fees: Neon Therapeutics; Financial Interests, Personal, Other, Consulting, Advisory Role, Research Funding and Travel fees: Novartis; Financial Interests, Personal, Other, Consulting, Advisory Role, Research Funding and Travel fees: Novocure; Financial Interests, Personal, Other, Consulting, Advisory Role, Research Funding and Travel fees: Pfizer; Financial Interests, Personal, Other, Consulting, Advisory Role, Research Funding and Travel fees: PharmaMar; Financial Interests, Personal, Other, Consulting, Advisory Role, Research Funding and Travel fees: Puma Biotechnology; Financial Interests, Personal, Other, Consulting, Advisory Role, Research Funding and Travel fees: Regeneron; Financial Interests, Personal, Other, Consulting, Advisory Role, Research Funding and Travel fees: Roche/Genentech; Financial Interests, Personal, Other, Consulting, Advisory Role, Research Funding and Travel fees: Sanofi-Aventis; Financial Interests, Personal, Other, Consulting, Advisory Role, Research Funding and Travel fees: Seattle Genetics; Financial Interests, Personal, Other, Consulting, Advisory Role, Research Funding and Travel fees: Takeda; Financial Interests, Personal, Other, Consulting, Advisory Role, Research Funding and Travel fees: Tesaro; Financial Interests, Personal, Other, Consulting, Advisory Role, Research Funding and Travel fees: Transgene; Financial Interests, Personal, Other, Consulting, Advisory Role, Research Funding and Travel fees: Triptych Health Partners; Financial Interests, Personal, Other, Consulting, Advisory Role, Research Funding and Travel fees: TRM Oncology. M. Thomas: Financial Interests, Personal, Other, Speaker Honoraria, Consulting and Advisory Role fees, Research Funding and Travel Support: AbbVie; Financial Interests, Personal, Other, Speaker Honoraria, Consulting and Advisory Role fees, Research Funding and Travel Support: AstraZeneca; Financial Interests, Personal, Other, Speaker Honoraria, Consulting and Advisory Role fees, Research Funding and Travel Support: Bristol Myers Squibb; Financial Interests, Personal, Other, Speaker Honoraria, Consulting and Advisory Role fees, Research Funding and Travel Support: Boehringer Ingelheim; Financial Interests, Personal, Other, Speaker Honoraria, Consulting and Advisory Role fees, Research Funding and Travel Support: Celgene; Financial Interests, Personal, Other, Speaker Honoraria, Consulting and Advisory Role fees, Research Funding and Travel Support: Chugai; Financial Interests, Personal, Other, Speaker Honoraria, Consulting and Advisory Role Fees, Research Funding and Travel Support: Lilly; Financial Interests, Personal, Other, Speaker Honoraria, Consulting and advisory role fees, Research Funding and Travel Support: Merck Sharp & Dohme; Financial Interests, Personal, Other, Speaker Honoraria, Consulting and Advisory Role fees, Research Funding and Travel Support: Novartis; Financial Interests, Personal, Other, Speaker Honoraria, Consulting and Advisory Role fees, Research Funding and Travel Support: Pfizer; Financial Interests, Personal, Other, Speaker Honoraria, Consulting and Advisory Role fees, Research Funding and Travel Support: Roche; Financial Interests, Personal, Other, Speaker Honoraria, Consulting and Advisory Role fees, Research Funding and Travel Support: Takeda. V. Velcheti: Financial Interests, Personal, Other, Consulting and Advisory Role fees and Research Funding: Alkermes; Financial Interests, Personal, Other, Consulting and Advisory Role fees and Research Funding: Altor Bioscience; Financial Interests, Personal, Other, Consulting and Advisory Role fees and Research Funding: Altreca; Financial Interests, Personal, Other, Consulting and Advisory Role fees and Research Funding: AstraZeneca/MedImmune; Financial Interests, Personal, Other, Consulting and Advisory Role fees and Research Funding: Boston Scientific; Financial Interests, Personal, Other, Consulting and Advisory Role fees and Research Funding: Bristol Myers Squibb; Financial Interests, Personal, Other, Consulting and Advisory Role fees and Research Funding: Eisai; Financial Interests, Personal, Other, Consulting and Advisory Role fees and Research Funding: EMD Serono; Financial Interests, Personal, Other, Consulting and Advisory Role fees and Research Funding: Genentech; Financial Interests, Personal, Other, Consulting and Advisory Role fees and Research Funding: Genoptix; Financial Interests, Personal, Other, Consulting and Advisory Role fees and Research Funding: GlaxoSmithKline; Financial Interests, Personal, Other, Consulting and Advisory Role fees and Research Funding: Heat Biologics; Financial Interests, Personal, Other, Consulting and Advisory Role fees and Research Funding: Leap Therapeutics; Financial Interests, Personal, Other, Consulting and Advisory Role fees and Research Funding: Merck; Financial Interests, Personal, Other, Consulting and Advisory Role fees and Research Funding: Foundation Medicine; Financial Interests, Personal, Other, Consulting and Advisory Role fees and Research Funding: Lilly; Financial Interests, Personal, Other, Consulting and Advisory Role fees and Research Funding: Nantworks; Financial Interests, Personal, Other, Consulting and Advisory Role fees and Research Funding: Novartis; Financial Interests, Personal, Other, Consulting and Advisory Role fees and Research Funding: Novocure; Financial Interests, Personal, Other, Consulting and Advisory Role fees and Research Funding: OncoPlex Diagnostics; Financial Interests, Personal, Other, Consulting and Advisory Role fees and Research Funding: RSIP Vision; Financial Interests, Personal, Other, Consulting and Advisory Role fees and Research Funding: Trovagene. E. Zhi: Financial Interests, Personal, Full or part-time Employment: GlaxoSmithKline; Financial Interests, Personal, Ownership Interest: GlaxoSmithKline. M. Whipple Neibauer: Financial Interests, Personal, Full or part-time Employment: GlaxoSmithKline; Financial Interests, Personal, Ownership Interest: GlaxoSmithKline; Financial Interests, Personal, Ownership Interest: Merck. A. Stojadinovic: Financial Interests, Personal, Full or part-time Employment: GlaxoSmithKline; Financial Interests, Personal, Ownership Interest: GlaxoSmithKline. S. Peters: Consultation / Advisory role: AbbVie, Amgen, AstraZeneca, Bayer, Beigene, Biocartis, Bio Invent, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, Elsevier, F. Hoffmann-La Roche/Genentech, Foundation Medicine, Illumina, Incyte, IQVIA, Janssen, Medscape, Merck Sharp & Dohme, Merck Serono, Merrimack, Mirati, Novartis, PharmaMar, Phosplatin Therapeutics, Pfizer, Regeneron, Sanofi, Seattle Genetics, Takeda, Vaccibody Talk in a company’s organized public event: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, e-cancer, Eli Lilly, F. Hoffmann-La Roche/Genentech, Illumina, Medscape, Merck Sharp & Dohme, Novartis, PER, Pfizer, Prime, RTP, 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/Genentech, GSK, Illumina, Lilly, Merck Sharp & Dohme, Merck Serono, Mirati, Novartis, and Pfizer, Phosplatin Therapeutics.

Background

Lynch syndrome (LS) is the most prevalent inherited cause of genetic predisposition to colorectal cancer (CRC) by accounting for approximately 1-3% of all newly diagnosed CRC cases. LS includes, beyond CRC, a broad spectrum of associated cancers, with different genetic etiology and risk, including endometrial, gastric, small bowel, ovarian, pancreas, hepato-biliary tract, urinary tract, and brain tumors. Individuals affected by LS show an increased lifetime cumulative risk of CRC (25-80%). The LS is caused by germline pathogenic variants (PVs) in one of four MMR genes, such as MLH1, MSH2, MSH6, PMS2, or in EPCAM gene. The choice of the most suitable criteria and optimal screening strategy for selecting subjects to undergo germline genetic testing are still debated.

Methods

The aim of our work was to evaluate the most suitable selection mode for identifying LS-related CRC patients through different approaches, in order to increase diagnostic power of this hereditary disorder. We retrospectively harvested and analyzed all clinical and pathological information of 854 CRC patients, enrolled at the University Hospital Policlinico “P. Giaccone” of Palermo (Italy), 87 of which were subjected to germline MMR testing based on Amsterdam criteria II and revised Bethesda guidelines, in order to assess the prevalence and typology of different inherited MMR variants detected in LS patients.

Results

Our study revealed that 25 (28.7%) out of 87 CRC patients harboured germline PVs/LPVs in MMR genes, whereas 62 patients were wild-type. No mutation was detected in EPCAM gene. In particular, we found that MSH2 and MLH1 were the more frequently altered genes. MSH2 PVs were mainly associated to CRC women who had developed also endometrial cancers. The best selection approach has proven to be the analysis of tissue microsatellite instability (MSI) status according to the revised Bethesda guidelines.

Conclusions

The use of different approaches of selection is needed for identifying LS-related CRC patients, to reduce underdiagnosis of LS patients. The revised Bethesda guidelines showed a greater diagnostic power compared to Amsterdam criteria II.

Legal entity responsible for the study

University-Hospital Policlinico \"P. Giaccone\", Palermo, Italy.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Functional adaptive responses (i.e. due to cellular machinery modulations) could contribute to targeted treatment resistance. We hypothesize that understanding tumor cell adaptive responses induced by cabozantinib (C) in renal cell cancer (RCC) cells could provide a rational base for selecting treatment combinations and optimise drug doses and schedules.

Methods

We evaluated functional proteomic changes induced in VHL-mutated 786-O RCC cell line after in vitro exposure to low-dose C using reverse phase protein array (RPPA). A linear model analysis was performed on normalized intensity data from RPPA, in order to identify proteins and phosphoproteins undergoing significant treatment-induced changes. Then, we evaluated in vitro the efficacy of the interaction between C and drugs selected on the basis of RPPA analysis by mean of dose matrix tests.

Results

We exposed 786-O cells to HGF alone or in combination with C at 40 nM for 24 hours and then we performed RPPA analysis. Despite the low dose of C used, we observed a significant variation (i.e. with a log2 fold change for intensity of < 0.5 or > 1.5) in expression or phosphorylation of several protein targets. We observed inhibition of protein phosphorylation downstream of C targets (among which AXL, VEGFR−2, components of the PI3K/AKT/mTOR pathway and MEK1), which validates the cell model. Unexpectedly, we detected a significantly increased intensity signal for several protein targets involved in DNA repair process (RBBP8, RPA32_pS4_S8, BABAM1, BAP1, CDKN1A). We thus tested in vitro the association of C and inhibitors of the DNA repair proteins ATM, ATR and Wee1. We could observe that while the combination of C with KU60019 (an ATM inhibitor) is additive, the combinations of C with VE822 (an ATR inhibitor) or MK1775 (a Wee1 inhibitor) are synergistic in 2D and 3D cell culture.

Conclusions

Analysis of functional proteomic changes induced in vitro by C helped us to select targets for combination targeted therapy in RCC. Overall, our data suggest that cellular adaptive responses to drugs play a role in tumor resistance, and that elucidating them could help in designing drug combinations suitable for testing in the clinical setting.

Legal entity responsible for the study

Institut du Cancer de Montpellier, Université de Montpellier, Montpellier, France.

Funding

Ipsen.

Disclosure

D. Tosi: Other, Personal and Institutional, Research Grant: Ipsen; Other, Personal, Other, Travel support for scientific meetings: Ipsen. All other authors have declared no conflicts of interest.

Background

Long-term disease-free survival (LT-S) in pts with advanced high grade epithelial OC is poorly described. We recently reported that the 5yr DFS rate was <3% for pts with stage III/IV OC enrolled in 3 large 1st line trials (ESMO 2020). VIVROVAIRE enrolled LT-S OC pts (median DFS:6 yrs) regardless of stage and grade. Here we aimed to characterize the subset in VIVROVAIRE with LT-S and poor prognostic features (stage III/IV and high grade) and compare their immune profile to stage III/IV OC tumors from a neoadjuvant trial (CHIVA) with shorter survival (ST-S).

Methods

Tumors were centrally reviewed by an expert pathologist to confirm histology and grade. Staining for CK, CD3, CD8, FOXP3 was performed on the LT-S VIVROVAIRE tumors and compared to the control ST-S tumors from CHIVA (N=123). Cells were quantified in number/mm² and the ratio of effector to suppressor (CD8/FOXP3) calculated.

Results

68 high grade (serous, endometrioid or poorly differentiated) OC tumors with LT-S were identified including 28 stage I/II (median DFS: 52mo) and 37 stages III/IV (mDFS: 59mo), 3 NA. Within the LT-S cohort, Stage I/II had fewer CD8+ (median 32 vs 85; p=0.02) and FOXP3+ cells (median 3.5 vs 12; p=0.007) compared to Stage III/IV, however there was no difference in the CD8/FOXP3 ratio in localized vs advanced stage LT-S. We next compared the immune profile of stage III/IV LT-S to the ST-S. Median DFS in the ST-S Stage III/IV was 15mo, representative of an all-comer population with advanced stage OC in the pre-PARP inhibitor era. There was no significant difference in the total number of CD8+ T cells, however Stage III/IV LT-S had significantly fewer FOXP3+ cells (12 vs 29; p=0.02) and a much more favorable effector to suppressor cell ratio (median CD8/FOXP3= 11 vs 5; p=0.007) compared to ST-S.

Conclusions

We describe a unique cohort of OC pts with exceptional survivorship (median DFS of 5yrs) despite poor prognostic features (high grade and stage III/IV). A favorable effector/suppressor balance may contribute to their improved outcomes suggesting that targeting T-regulatory cells should be explored. Further studies are ongoing to decipher the immuno-genomic features associated with prolonged remission.

Clinical trial identification

NCT02323568.

Legal entity responsible for the study

The authors.

Funding

Canceropole (EMERGENCE).

Disclosure

O. Tredan: Financial Interests, Personal, Licensing Fees: Roche; Financial Interests, Personal, Licensing Fees: MSD; Financial Interests, Personal, Licensing Fees: AstraZeneca; Financial Interests, Personal, Licensing Fees: Novartis; Financial Interests, Personal, Licensing Fees: Pfizer; Financial Interests, Personal, Licensing Fees: Lilly; Financial Interests, Personal, Licensing Fees: Seagen; Financial Interests, Personal, Licensing Fees: Daiichi; Financial Interests, Personal, Licensing Fees: Eisai; Financial Interests, Personal, Licensing Fees: Pierre fabre; Financial Interests, Institutional, Research Grant: Roche; Financial Interests, Institutional, Research Grant: MSD; Financial Interests, Institutional, Research Grant: BMS. E. Kalbacher: Financial Interests, Personal and Institutional, Advisory Board: GSK; Financial Interests, Personal and Institutional, Advisory Board: AstraZeneca; Financial Interests, Personal and Institutional, Advisory Board: Roche; Financial Interests, Personal and Institutional, Advisory Board: Leopharma; Financial Interests, Personal and Institutional, Advisory Board: Bayer; Financial Interests, Personal and Institutional, Advisory Board: Sanofi; Financial Interests, Personal and Institutional, Advisory Board: Pharmamar. N. Dohollou: Financial Interests, Personal, Other: Amgen; Financial Interests, Personal, Research Grant: AstraZeneca; Financial Interests, Personal, Research Grant: BMS; Financial Interests, Personal, Research Grant: Boehringer; Financial Interests, Personal, Expert Testimony: Daiichi; Financial Interests, Personal, Research Grant: Genomic Health; Financial Interests, Personal, Expert Testimony, Research grant: Lilly; Financial Interests, Personal, Research Grant: MSD; Financial Interests, Personal, Research Grant: Novartis; Financial Interests, Personal, Research Grant: Pfizer; Financial Interests, Personal, Expert Testimony, Research grant: Roche; Financial Interests, Personal, Expert Testimony: Seagen. P. Pautier: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Institutional, Advisory Board: AstraZeneca; Financial Interests, Institutional, Advisory Board: Clovis; Financial Interests, Institutional, Advisory Board: GSK; Financial Interests, Personal, Advisory Board: Pharmamar; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Institutional, Advisory Board: Roche. A. Leary: Financial Interests, Personal, Advisory Board: GSK; Financial Interests, Personal, Advisory Board: Clovis; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Biocad; Financial Interests, Personal, Advisory Board: Seattle Genetics; Financial Interests, Personal, Advisory Board: Ability. All other authors have declared no conflicts of interest.

Background

Unresectable advanced sinonasal epithelial tumors are rare diseases having an overall dismal prognosis (5-year reported PFS less than 15%). No standard treatment is recognized. This prospective study explored the safety and activity of a multimodality treatment modulated by histology, molecular profile and response to IC.

Methods

Pts with untreated inoperable squamous cell carcinoma (SCC), p53 wild-type intestinal type adenocarcinoma (ITAC), sinonasal undifferentiated and neuroendocrine carcinoma (SNUC; SNEC) and Hyams grade III olfactory neuroblastoma (ONB) were enrolled in a single-arm, open-label, phase II, multicenter clinical trial between 2013 and 2018. For each pt, a multidisciplinary team evaluated the best curative treatment. Pts were treated with up to 5 IC cycles, whose regimen was selected according to histotype. Photon and/or proton/carbon ion-based RT was employed according to disease site, stage and IC response. Primary endpoint was 5-year PFS, secondary endpoints were overall survival (OS), radiological response as per RECIST 1.1, safety.

Results

Out of 27 enrolled pts, 25 resulted evaluable for primary endpoint. One pts withdrew from the trial and another one was discontinued by the investigator. Five-year PFS was 26.8% (95% CI 12.6 – 57.1), with a median PFS of 18 months. Five-year OS was 23.8% (95% CI, 9.5 – 59.3), with a median OS of 27 months. The overall response rate to IC was 40%, representing a prognostic factor for 5-yr OS (33.3% in pts with response to IC vs 17.9% in pts without response to IC). Overall treatment safety was in line with multimodality intensive head and neck cancer treatments (3% of pts with G3-4 adverse event during IC). At a median follow up of 27 months, 5 G3-4 RT induced late adverse events have been recorded (1 case of G3 neurotoxicity, 2 cases of G3 hearing impairment, 2 cases of G3 xerostomia). No toxic deaths were recorded.

Conclusions

Multimodal combination of IC and innovative RT provide survival rates only slightly greater than previous experiences, underscoring the need for further treatment improvement. Response to IC confirmed its predictive value on survival. The overall treatment safety is acceptable.

Clinical trial identification

NCT02099188.

Legal entity responsible for the study

The authors.

Funding

Supported by Fondazione Regionale per la Ricerca Biomedica.

Disclosure

P. Bossi: Financial Interests, Institutional, Research Grant: GlaxoSmithKline, MSD, Sanofi, Bristol Myers Squibb. C. Resteghini: Financial Interests, Personal, Advisory Board: Sun Pharma. B. Vischioni: Financial Interests, Personal, Invited Speaker: Merck. N. Facchinetti: Financial Interests, Institutional, Sponsor/Funding: Helsinn Healthcare SA. L.F. Licitra: Financial Interests, Institutional, Research Grant: AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Celgene International, Debiopharm International SA, Eisai, Exelixis inc, Hoffmann-La Roche ltd, IRX Therapeutics inc, Medpace inc, Merck–Serono, MSD, Novartis, Pfizer, Roche.; Financial Interests, Personal, Advisory Role: AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, MSD, Merck–Serono, Boehringer Ingelheim, Novartis, Roche, Debiopharm International SA, Sobi, Ipsen, Incyte Biosciences Italy srl, Doxa Pharma, Amgen, Nanobiotics Sa and GlaxoSmithKline. All other authors have declared no conflicts of interest.