PRODIGE 23, a phase III clinical trial, investigated the role of neoadjuvant mFOLFIRINOX before preoperative chemoradiation (CRT), with TME-surgery and adjuvant chemotherapy (CT) in resectable T3-4 rectal cancer.
Eligible pts had cT3-T4 M0 rectal cancers, <76 years, and WHO PS ≤1. Primary endpoint was 3-yr DFS. Secondary endpoints were ypT0N0 rate, OS, metastasis-free survival (MFS) and QoL assessed with EORTC QLQ-C30 and QLQ-CR29. 460 pts were needed to observe 136 events to increase 3-year DFS from 75% to 85% (HR=0.56). Arm A pts received preop CRT (50 Gy, 2 Gy/fr + capecitabine), surgery, then adjuvant CT for 6 mos. Arm B pts received 6 cycles of mFOLFIRINOX, followed by the same preop CRT, surgery and 3 mos of adjuvant CT. Adjuvant CT consisted of mFOLFOX6 or capecitabine.
(ITT) From 2012 to 2017, 230/231 pts were randomly assigned in Arm A/B. Median follow-up was 46.5 mos and 136 DFS events occurred. Main results are reported in the table below. Time to QoL deterioration ≥ 10 points was significantly longer in Arm A for chemotherapy symptoms (hair loss, fatigue, nausea/vomiting, appetite loss, diarrhea, dry mouth, taste) and worry about weight, and was significantly longer in Arm B for functional outcomes as dysuria (HR 0.61, p<0.01), buttock pain (HR 0.7, p=0.01), fecal incontinence (HR 0.73, p=0.05), sore skin (HR 0.67, p<0.01), bowel embarrassment (HR 0.73, p=0.05) and impotence in men (HR 0.64, p<0.01).
Control arm, % Experimental arm, % HR and p values 3yr DFS 68.5 75.7 0.69 (0.49-0.097), P=0.034 3 yr MFS 71.7 78.8 0.64 (0.44-0.93), P<0.02 Primary tumor resection rate 93.5 92.2 Ns Type of resection - Low anterior or intersphincteric - Abdominoperineal 85.1 14 85.9 14.1 Ns TME, complete mesorectum 94.9 96.3 Ns Postoperative mortality 2.8 0 P=0.03 Overall morbidity 31.2 29.3 Ns Median hospital stay, days 12 11 Ns Median n0 of postop RBCs 0 0 Ns ypT0N0 12.1 27.8 P<0.001 R0/ R1-R2 94.4/5.6 95.3/4.7 Ns
Neoadjuvant mFOLFIRINOX plus CRT is safe, preserves the quality of resection and significantly increased ypCR rate, DFS, and MFS. Patients treated with neoadjuvant chemotherapy had more symptoms during chemotherapy, but benefits from longer time to QoL deterioration for rectal functional outcomes.
NCT01804790.
R&D UNICANCER.
French National Cancer Institute, French National League Against Cancer.
C. Borg: Research grant/Funding (institution): Roche; Advisory/Consultancy: MSD; Advisory/Consultancy: Roche; Advisory/Consultancy: Servier; Advisory/Consultancy: Pierre Fabre; Travel/Accommodation/Expenses: Amgen; Travel/Accommodation/Expenses: MSD; Travel/Accommodation/Expenses: Bayer. P-L. Etienne: Research grant/Funding (institution): Bristol Meyers Squibb; Travel/Accommodation/Expenses: Sanofi; Travel/Accommodation/Expenses: Ipsen; Travel/Accommodation/Expenses: Novartis; Travel/Accommodation/Expenses: Roche; Travel/Accommodation/Expenses: Amgen. V. Boige: Research grant/Funding (institution): Merck Serono; Advisory/Consultancy: Eisai; Advisory/Consultancy: Ipsen; Advisory/Consultancy: BMS; Advisory/Consultancy: Bayer; Advisory/Consultancy: Merck Serono; Travel/Accommodation/Expenses: Bayer; Travel/Accommodation/Expenses: Merck Serono; Travel/Accommodation/Expenses: Roche; Travel/Accommodation/Expenses: Sanofi. C. Louvet: Advisory/Consultancy: MSD; Advisory/Consultancy: Halozyme; Advisory/Consultancy: Roche; Advisory/Consultancy: Celgene; Travel/Accommodation/Expenses: MSD; Travel/Accommodation/Expenses: Roche. All other authors have declared no conflicts of interest.
Watchful waiting without surgery for rectal cancer is an option after complete response to chemoradiation. There is a need for optimising patient selection and radiotherapy to cure more patients with this modality. The aim of the study was to test high-dose radiotherapy of low rectal cancer for organ preservation in a multi-centre setting. The early endpoint of clinical complete response (cCR) at 12 weeks is reported here.
This prospective trial enrolled patients with rectal cancer 0-6 cm from the anal verge, T1-3 N0-1 M0, performance status 0-2, and adequate organ function. Radiotherapy consisted of 62 and 50.4 Gy to the tumour and regional lymph nodes, respectively, in 28 fractions using intensity-modulated radiation therapy and daily image guidance. Capecitabine 825mg/m2 BID was administered on treatment days. Patients with cCR 6-12 weeks from end of treatment judged by MRI, endoscopy, and digital rectal exam were referred to observation without surgery. The patients continue follow-up for recurrence, adverse events, and patient reported outcomes irrespective of treatment.
Three Danish centres enrolled 108 patients from 9/2015 to 12/2019; with 15%/54%/31% T1/T2/T3 tumours; median tumour distance from anal verge 4.5 cm; 29% with N1 disease; 36% female; median age 71 years. 107 patients started treatment, the majority receiving full dose of radiotherapy (n=104) and of chemotherapy (n=80). The most frequent grade 3-4 toxicities were diarrhoea (7%), constipation (2%), and nausea, vomiting, pain, and skin reaction (all 1%). One patient died from other causes and one left the study before evaluation. 12 weeks after end of treatment, 13 patients had residual tumour and were referred for surgery; two had distant metastasis leaving 90 of 108 patients (83.3%) with cCR and allocation to follow-up without surgery.
The unprecedented high cCR rate of 83.3% in this multicentre phase II trial demonstrates that rectal cancer patients can be offered curative chemoradiation. Long-term outcomes, including tumour control, organ function, and quality of life, are still needed to evaluate the full potential of high-dose 62 Gy radiotherapy as a new standard treatment.
NCT02438839.
The authors.
Danish Cancer Society.
L.H. Jensen: Research grant/Funding (institution): MSD, InCyte, 2cureX, BMS. All other authors have declared no conflicts of interest.
Pooled analysis of International Duration Evaluation of Adjuvant therapy (IDEA) did not demonstrate the non-inferiority of 3- vs. 6-month (m) adjuvant FOLFOX/CAPOX for disease-free survival (DFS) in stage III colon cancer (CC) patients. However, in patients treated with CAPOX (especially low-risk patients), 3-m therapy had similar efficacy as the 6-m one. Herein, we report the overall survival (OS) and long-term DFS for the ACHIEVE trial, as part of the IDEA collaboration.
ACHIEVE was a randomized, open-label, multicenter study that allocated stage III CC patients to 3-m or 6-m mFOLFOX6/CAPOX post-surgery. Hazard ratios (HRs) for the association between survival endpoints and treatment duration (3 m or 6 m) were analyzed using the Cox model. Pre-planned confirmatory sub-group analyses included regimens and risk groups.
As of September 2019, 175 deaths and 323 DFS events were observed in the modified intention-to-treat population (n=1,291), with an overall median survival follow-up of 62 m. Seventy-five percent of the patients received CAPOX. Fifty-six percent were low-risk (T1-3 and N1), while 44% were high-risk (T4 or N2). The 5-yr OS rate was 87% (95% confidence interval [CI], 84–90%) and 87% (84–89%) in the 3-m and 6-m therapy groups, respectively, with an estimated HR of 0.90 (0.67–1.21). The 5-year DFS rate was 75% (72–78%) and 74% (71–78%) in the 3- and 6-m therapy groups, respectively, with an estimated HR of 0.94 (0.76–1.18). For the HRs (95% CI) in the pre-planned subgroup analyses, please refer to the table.
OS DFS 0.87 (0.61, 1.24) 0.93 (0.72, 1.21) 0.95 (0.56, 1.61) 0.98 (0.67, 1.46) 0.88 (0.53, 1.47) 0.88 (0.60, 1.30) 0.94 (0.65, 1.35) 1.02 (0.79, 1.33)
Our data indicate that previous heterogeneous DFS results based on regimens and risk groups became almost the same; the OS and DFS of 3-m and 6-m groups were comparable. Three-month adjuvant CAPOX therapy could be used for most stage III CC patients, but our results should be interpreted in the context of the whole IDEA collaboration.
UMIN000008543.
The authors.
Yakult Honsha.
T. Yoshino: Research grant/Funding (institution): Novartis Pharma K.K.; Research grant/Funding (institution): MSD.K.K.; Research grant/Funding (institution): Sumitomo Dainippon Pharma Co., Ltd.; Research grant/Funding (institution): Chugai Pharmaceutical Co., Ltd.; Honoraria (institution): Sanofi K.K.; Research grant/Funding (institution): Daiichi Sankyo Company, Limited; Research grant/Funding (institution): Parexel International Inc.; Research grant/Funding (institution): Ono Pharmaceutical Co., Ltd.; Research grant/Funding (institution): GlaxoSmithKline K.K.. M. Kotaka: Honoraria (self): Chugai Pharmaceutical; Honoraria (self): Yakult Honsha; Honoraria (self): Takeda Pharmaceutical. M. Nakamura: Speaker Bureau/Expert testimony: Chugai Co.Ltd.; Speaker Bureau/Expert testimony: Yakult Honsya Co. Ltd.. T. Kato: Honoraria (self), Research grant/Funding (institution): Chugai Pharmaceutical Co., Ltd; Honoraria (self): Takeda Pharmaceutical Company Limited; Honoraria (self): Eli Lilly; Honoraria (self): Bayer Yakuhin; Honoraria (self): Sanofi; Honoraria (self): Yakult Honsha. T. Mizushima: Speaker Bureau/Expert testimony: EA Pharma Co., Ltd.; Speaker Bureau/Expert testimony: AbbVie GK.; Speaker Bureau/Expert testimony: Miyarisan Pharmaceutical Co. Ltd.; Speaker Bureau/Expert testimony: Janssen Pharmaceutical K.K; Speaker Bureau/Expert testimony: Kyorin Pharmaceutical Co., Ltd.; Speaker Bureau/Expert testimony: Daiichi Sankyo Company, Limited.; Speaker Bureau/Expert testimony, Research grant/Funding (institution): Mitsubishi Tanabe Pharma Corporation; Speaker Bureau/Expert testimony: Takeda Pharmaceutical Company Limited; Research grant/Funding (institution): Taiho Pharmaceutical Co., Ltd.; Research grant/Funding (institution): Chugai Pharmaceutical Co., Ltd.; Research grant/Funding (institution): Sanofi K.K.; Research grant/Funding (institution): Astellas Pharma Inc.; Research grant/Funding (institution): Shionogi & Co., Ltd.. T. Yamanaka: Honoraria (self), Research grant/Funding (institution): Chugai; Honoraria (self), Research grant/Funding (institution): Takeda; Honoraria (self), Research grant/Funding (institution): Taiho; Honoraria (self), Research grant/Funding (institution): Boehringer-Ingelheim; Honoraria (self), Research grant/Funding (institution): Bayer; Honoraria (self): Pfizer; Advisory/Consultancy: Gilead Sciences; Advisory/Consultancy, Research grant/Funding (institution): Daiichi-Sankyo; Advisory/Consultancy: Huya Biosciences; Advisory/Consultancy: Sysmex; Research grant/Funding (institution): Ono; Research grant/Funding (institution): Merck Serono; Research grant/Funding (institution): Astellas; Research grant/Funding (institution): Eli Lilly. A. Ohtsu: Honoraria (self), Research grant/Funding (institution): BMS; Honoraria (self): Ono; Honoraria (self): Taiho; Honoraria (self): Chugai. All other authors have declared no conflicts of interest.
Advanced squamous cell anal carcinoma (advSCAC) is a rare disease with no standard therapies beyond first line currently available. Case series and phase I and II prospective studies have documented respectively promising activity of the anti-EGFR cetuximab (CET) and of immunotherapy in chemorefractory advSCAC. In this study, we aimed to evaluate activity and safety of avelumab (AVE) alone or in combination with CET in pretreated advSCAC.
This was an open-label, “pick the winner”, prospective, multicenter randomized phase 2 trial (NCT03944252). Patients (pts) with mSCAC who had progressed after at least one line of treatment were randomized 1:1 to receive either AVE (arm A) or AVE+CET (arm B). A Simon’s two-stage Mini-Max design was used. Primary endpoint was overall response rate (ORR). The null hypothesis that the true response rate was 5% (
60 pts were enrolled, 30 in each arm. Median age was 63 years; M/F distribution was 19/41. All baseline characteristics were well balanced between the two arms. At a median follow up of 11 months, 5 patients out of 30 showed PR in arm B, reaching the primary endpoint. ORR was 10% (95% CI 2.5 - 27) and 17% (95% CI 6.3 – 34,1) in arm A and B, respectively; Disease control rate (DCR) was 50% (95% CI 35.3 – 71.3) in arm A and 57% (95% CI 42.4 – 77.6) in arm B. Median PFS was 2.05 months (95% CI 1.84 – 5.52) in arm A and 3.88 months (95% CI 2.07 – 6.14) in arm B. Median OS data were not yet mature. The most common treatment related adverse event (TRAE) were fatigue in Arm A (17%) and skin and subcutaneous disorders in arm B (87%); 2 patients (7%) in arm B permanently interrupted the treatment due to TRAE; no permanent interruptions due to TRAE were observed in arm A.
The CARACAS Study met its primary endpoint in patients receiving AVE+CET (arm B), with promising activity of dual EGFR and PD-L1 blockade in advSCAC deserving further investigation. A favourable safety profile was observed in both of the study arms.
NCT03944252.
Veneto Institute of Oncology IOV – IRCCS.
Veneto Institute of Oncology IOV - IRCCS; GONO - Gruppo Oncologico Nord Ovest; Pharmaceutical/Biotech Company: Merck Serono.
S. Lonardi: Advisory/Consultancy: Amgen; Lilly; Merck Serono; Servier; Speaker Bureau/Expert testimony: Bristol-Myers Squibb; Lilly; Merck Serono; Roche; Servier; Research grant/Funding (self): Amgen; Merck Serono;. F. Pietrantonio: Advisory/Consultancy: Amgen; Bayer; Lilly; Merck Serono; Roche; Sanofi; Servier; Research grant/Funding (self): Bristol-Myers Squibb. V. Formica: Honoraria (self): Amgen; Servier. M. Scartozzi: Advisory/Consultancy: Amgen; Bayer; Bristol-Myers Squibb; Celgene; Eisai; Merck Serono; Sanofi; Speaker Bureau/Expert testimony: Amgen; Bayer; Eisai; Merck Serono; Roche/Genentech; Servier; Research grant/Funding (self), Research grant/Funding (institution): Bayer; Celgene (Inst); Merck Serono (Inst); Merck Sharp & Dohme (Inst); Sanofi (Inst); Travel/Accommodation/Expenses: Celgene; Merck Serono; Servier. V. Zagonel: Advisory/Consultancy: Bristol-Myers Squibb; Merck; Speaker Bureau/Expert testimony: Astellas Pharma; AstraZeneca; Bayer; Bristol-Myers Squibb; Lilly; Roche; Servier laboratories Ltd; Travel/Accommodation/Expenses: Bayer; Roche; Servier laboratories Ltd. All other authors have declared no conflicts of interest.
Immune checkpoint blockade agents targeting PD-1/PD-L1 as monotherapy are associated with responses in 10-25% of patients (pts) with metastatic human papillomavirus (HPV)-associated malignancies. VEGF signaling has been linked with immune evasion and suppression within the tumor microenvironment as a possible resistance mechanism to immunotherapy. The combination of the anti-PD-L1 antibody atezolizumab (A) and anti-VEGF antibody bevacizumab (B) demonstrated survival benefit in virally linked hepatocellular carcinoma. Here we evaluated the combination of A and B for pts with unresectable HPV-associated cancers.
Pts with previously treated, immunotherapy-naïve HPV-associated cancers were eligible for this single-arm phase II study. Pts received A (1200 mg) and B (15 mg/kg) intravenously every 3 weeks until development of progressive disease or drug intolerance. Responses were evaluated every 9 weeks by RECIST Criteria v1.1. The primary objective was to measure best overall response rate (ORR). Pretreatment and on-treatment biopsies were collected for biomarker analyses.
20 pts with unresectable squamous cell carcinoma of the anal canal were treated with A+B (median number of doses, 6). Median age was 59 years (range, 43-80). 60% of pts had received only 1 prior line of therapy. Partial responses, both verified, were seen in 2 pts (ORR 10%, 95% confidence interval (CI): 1.2-32), with stable disease in 11 (55%) pts. Median progression-free survival (PFS) was 4.1 months (95% CI: 2.6-NA). 12-month PFS rate was 20% (95% CI: 8-52). Median overall survival (OS) was 11.6 months (95% CI, 9.5-20). Grade ≥3 adverse events (AE) were observed in 7 (35%) pts, with one grade 5 treatment-related AE (bowel perforation). The most common grade ≥3 AEs were hyponatremia (N=4), infection (N=2), and hypertension (N=2). Updated biomarker analyses will be presented.
A + B displays potential clinical benefit for pts with treatment-refractory metastatic anal cancer. Further investigation to immunotherapy combination trials is warranted to build upon outcomes with immune checkpoint monotherapies. Ongoing correlative studies may identify predictive biomarkers associated with benefit for this combination.
NCT03074513.
The University of Texas M.D. Anderson Cancer Center.
Genentech.
V. Morris: Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Bristol-Myers Squibb; Research grant/Funding (institution): EMD Serono; Research grant/Funding (institution): Immatics; Advisory/Consultancy: Array Biopharma; Advisory/Consultancy, Data safety monitoring board: Incyte. I.I. Wistuba: Honoraria (self), Research grant/Funding (self): Genentech; Honoraria (self), Research grant/Funding (self): Bayer; Honoraria (self), Research grant/Funding (self): AstraZeneca/Medimmune; Honoraria (self), Research grant/Funding (self): Pfizer; Honoraria (self), Research grant/Funding (self): HTG Molecular; Honoraria (self): Asuragen; Honoraria (self), Research grant/Funding (self): Merck; Honoraria (self): GlaxoSmithKline; Honoraria (self): GuardantHealth; Honoraria (self): Oncocyte; Honoraria (self): MSD; Research grant/Funding (self): Oncoplex; Research grant/Funding (self): DepArray; Research grant/Funding (self): Bristol-Myers Squibb; Research grant/Funding (self): Adaptive; Research grant/Funding (self): Adaptimmune; Research grant/Funding (self): EMD Serono; Research grant/Funding (self): Takeda; Research grant/Funding (self): Amgen; Research grant/Funding (self): Karus; Research grant/Funding (self): Johnson & Johnson; Research grant/Funding (self): Iovance; Research grant/Funding (self): 4D; Research grant/Funding (self): Novartis; Research grant/Funding (self): Akoya. P. Hwu: Research grant/Funding (institution): GlaxoSmithKline; Officer/Board of Directors: Immatics; Research grant/Funding (institution): Sanofi; Research grant/Funding (institution): Dragonfly. J.C. Yao: Research grant/Funding (self): Ipsen; Research grant/Funding (self): Chiasma; Research grant/Funding (self): Hutchinson Medi Pharma; Research grant/Funding (self): Advanced Accelerator Applications; Research grant/Funding (self): Novartis; Research grant/Funding (self): Tarveda; Research grant/Funding (self): Crinetics. D. Halperin: Research grant/Funding (institution): Genentech; Research grant/Funding (self): Tarveda; Advisory/Consultancy, Research grant/Funding (self): Advanced Accelerator Applications; Advisory/Consultancy, Research grant/Funding (self): Lexicon; Research grant/Funding (self): Incyte; Research grant/Funding (self): ThermoFisher; Advisory/Consultancy: Ipsen; Advisory/Consultancy: Curium. All other authors have declared no conflicts of interest.
Dihydropyrimidine dehydrogenase (DPD) deficiency is the main cause of severe FP-tox. DPD expression is regulated at post-transcriptional level by miR-27a.
Eligibility criteria included unbiased recruitment of Caucasian pts without FP dose adjustment based on DPD status. Main endpoint was hematological or digestive G4-5 FP-tox at 12 weeks. A clinical logistic regression model including age, sex, body mass index, FP administration (bolus±continuous
Full clinical data,
This IPD-MA on
CRD 42017058148.
The authors.
French Cancer Institute & French Health Ministry (PHRC-K 14-193 \"FUSAFE\") and French Ligue Contre le Cancer.
M-C. Etienne-Grimaldi: Honoraria (self), Travel/Accommodation/Expenses: Amgen. V. Boige: Honoraria (self), Advisory/Consultancy: Bayer; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Merck Serono; Honoraria (self): Amgen; Advisory/Consultancy, Travel/Accommodation/Expenses: Sanofi; Travel/Accommodation/Expenses: Daiichi Sankyo; Honoraria (self): Roche; Honoraria (self): MSD; Honoraria (self), Advisory/Consultancy: Ipsen; Advisory/Consultancy: Prestizia; Honoraria (self), Advisory/Consultancy: Eisai. D. Meulendijks: Shareholder/Stockholder/Stock options, Full/Part-time employment: AstraZeneca. C. Palles: Advisory/Consultancy: Oxford Cancer Biomarkers. U. Zanger: Licensing/Royalties: Robert Bosch GmbH. J. Taieb: Advisory/Consultancy: Amgen; Honoraria (self): Lily; Advisory/Consultancy: Sanofi; Honoraria (self): Roche; Advisory/Consultancy: Merk; Honoraria (self), Advisory/Consultancy: MSD; Honoraria (self): Celgene; Advisory/Consultancy: Servier; Honoraria (self): Sirtex; Advisory/Consultancy: Pierre Fabre. E. Gross: Licensing/Royalties, Method for predicting treatment response in breast cancer: Patent pending. All other authors have declared no conflicts of interest.
Typically, most patients with mCRC are incurable. However, a minority of patients who undergo complete metastasectomy attain cure. In particular, up to 75% of oligometastatic CRC patients develop recurrence post-resection. Existing data in the oligometastatic setting has shown that the efficacy of postoperative adjuvant treatment is limited and is largely extrapolated from earlier stages. Establishing prognosis after oligometastatic resection is difficult and thus a need exists for a better prognostic marker. Circulating tumour DNA (ctDNA) has been shown to identify minimal residual disease (MRD) and the risk of recurrence in early-stage disease. In this study, we present the largest clinical experience of MRD testing in the oligometastatic setting.
Tumour tissue and serial plasma samples were collected from CRC patients undergoing resection of metastases with curative intent as part of the PREDATOR study. A personalized and tumour-informed multiplex PCR assay (Signatera™ bespoke mPCR NGS assay) was used for the detection and quantification of ctDNA for post-resection MRD assessment. The study evaluated the prognostic value of ctDNA correlating MRD status with clinical outcomes.
A total of 100 patients were analysed. Post-oligometastatic resection, adjuvant therapy was given to 38% of the patients at the discretion of the treating physician. Post-surgery, MRD-positivity was observed in 52% (52/100) of patients, of which 86.5% (45/52) eventually relapsed (HR: 4.6; 95%CI: 2.6-8.1;
This study validates personalized ctDNA-based MRD status as the most significant biomarker for prognosis in patients with oligometastatic CRC. This biomarker may offer the clinical utility of guiding adjuvant treatment decisions in the oligometastatic setting and of informing future trial design.
Fotios Loupakis.
Amal.
F. Loupakis: Advisory/Consultancy: Amal. S. Sharma, D. Renner, S. Shchegrova, H. Sethi, B. Zimmermann, A. Aleshin: Full/Part-time employment: Natera. All other authors have declared no conflicts of interest.
Monitoring plasma ctDNA in localized CC detects MRD and patients at higher risk of recurrence. Tumor-only sequencing, without a deep prior knowledge of studied genes, may confounds germline with somatic variants. Consequently, up to 11% of patients cannot be tracked due to the absence of known somatic mutations. We aim at enhancing sensitivity by identifying novel somatic variants sequencing paired tumor DNA and WBCs to monitor CC patients.
150 patients with localized CC were prospectively recruited from October 2015 to October 2017. A custom 29-gene panel based on the Qiaseq chemistry which includes Unique Molecular Identifier was designed. The panel contains recurrent mutated regions and genes in CC. DNA extracted from matched FFPE and WBCs samples was sequenced on NextSeq platform at 500X and 1500X. Data analysis was performed with an optimized in-house bioinformatics pipeline to reduce background noise in variant calling. Variant allele frequency (VAF) was limited to 5%. Variants were ranked attending to VAF. Known pathogenic variants were determined based on our knowledge somatic variant database. Statistical analysis included log-rank test, Fischer´s exact test and Kaplan-Meier curves.
All patients presented at least one cancer somatic mutation (CSM) trackable by ctDNA analysis. Known pathogenic mutations were found in only 134 (89.3%). The mean number of CSM versus pathogenic mutations were 14 and 2, respectively. We identified 12 recurrently mutated genes which did not concur when we considered both known and unknown CSM. In patients harboring only one pathogenic variant (29.3%), 34% of times did not coincide with the somatic variant with the highest VAF. In those with 2 pathogenic variants (60%), just 12.2% coincided with the highest CSM. After a median follow-up of 35.8 months, 19 patients recurred.
In localized CC, when only known pathogenic mutations were studied, almost 11% of cases could not be tracked. In contrast, targeted sequencing of matched tumor and WBCs samples revealed novel cancer CMS and increased the sensitivity to universally track MRD in plasma.
Andrés Cervantes.
Instituto de Salud Carlos III (PI15/02180 and PI18/01909).
A. Cervantes: Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Merck Serono; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Roche; Advisory/Consultancy, Research grant/Funding (institution): Takeda; Advisory/Consultancy, Research grant/Funding (institution): Beigene; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Bayer; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Servier; Advisory/Consultancy, Research grant/Funding (institution): Lilly; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy, Research grant/Funding (institution): Astelas; Research grant/Funding (institution): Genentech; Speaker Bureau/Expert testimony: Amgen; Speaker Bureau/Expert testimony: Foundation Medicine; Research grant/Funding (institution): Pierre Fabre; Research grant/Funding (institution): Fibrogen; Research grant/Funding (institution): Amcure; Research grant/Funding (institution): Sierra Oncology; Research grant/Funding (institution): Astra Zeneca; Research grant/Funding (institution): Medimmune; Research grant/Funding (institution): BMS; Research grant/Funding (institution): MSD; Officer/Board of Directors: Executive Board member of ESMO; Officer/Board of Directors: INCLIVA General and Scientific Director. All other authors have declared no conflicts of interest.