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  • American Society of Clinical Oncology (ASCO)  (6)
  • 1
    Online Resource
    Online Resource
    Predictive impact of RNF43 mutation (mut) in patients (pts) with pMMR/MSS BRAF V600E mutated metastatic colorectal cancer (mCRC) treated with target therapy (TT) or chemotherapy (CT).
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. 3569-3569
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 3569-3569
    Abstract: 3569 Background: Encorafenib plus cetuximab is a standard option in the treatment of BRAF V600E mut mCRC pts pre-treated with at least one systemic therapy. RNF43 is a negative regulator of WNT pathway. A recent study showed that RNF43 mutation is associated with better outcome among pMMR/MSS BRAF V600E mut mCRC patients treated with TT but not in an independent cohort of pts not treated with TT (Elez et al. Nat Med 2022). However, no comparison is available between TT vs CT as second-line (2L) treatment for pMMR/MSS BRAF V600E mut mCRC according to RNF43 mutational status. Methods: The predictive impact of RNF43 mut was evaluated in a real-life dataset of 126 pMMR/MSS BRAF V600E mut mCRC pts treated with TT (consisting of BRAF inhibitor + anti-EGFR antibody ± MEK inhibitor) vs CT ± target agent as 2L treatment. A cohort of 36 pts receiving TT after 2L was also analyzed. Results: Thirty-one (25%) and 95 (75%) out of 126 pMMR/MSS BRAF V600E mut tumours were RNF43 mut and RNF43 wt, respectively. In the RNF43 mut group 14 (45%) received CT and 17 (55%) TT; in the RNF43 wt group, 56 (59%) and 39 (42%) received CT and TT, respectively. Among RNF43 mut pts, those treated with TT reported longer PFS (7.1 vs 3.0 months, HR: 0.35 95%CI: 0.16-0.76, p = 0.006) and higher ORR (42% vs 0%, p = 0.009) than those receiving CT. On the other hand, no significant difference was observed among RNF43 wt patients in terms of PFS (4.3 vs 3.7 months, HR: 0.69 95% CI: 0.45-1.05, p = 0.080) and ORR (28% vs 16%, p = 0.24). However, no significant interaction between treatment effect and RNF43 mutational status was reported in terms of PFS (p interaction = 0.17) and ORR (p interaction = 0.96). After excluding 36 pts in the CT group that received TT after 2L, no interaction effect was observed also in terms of OS (p interaction = 0.53). However, among RNF43 mut pts, those treated with TT reported longer OS (16.5 vs 10.1 months; HR: 0.34 95% CI: 0.11-1.00, p = 0.049), while no significant difference was observed among RNF43 wt pts (10.6 vs 6.6 months; HR: 0.66 95% CI: 0.39-1.11; p = 0.12). In the group receiving TT after 2L, 9 (25%) out of 36 cases were RNF43 mut and achieved higher ORR (78% vs 26%, p = 0.014) and longer PFS (10.1 vs 4 months; HR: 0.35 95%CI: 0.14-0.88; p = 0.020) and OS (11.7 vs 7 months; HR: 0.35 95%CI: 0.15-0.82; p = 0.012) than RNF43 wt (N = 27). Conclusions: pMMR/MSS BRAF V600E mut mCRC patients achieve benefit from TT vs CT independently of RNF43 mutational status, but a higher magnitude of benefit from TT is observed among those with RNF43 mut tumors. These findings deserve confirmation in past and current randomized trials (i.e. BEACON and BREAKWATER).
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.16_suppl.3569
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
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  • 2
    Online Resource
    Online Resource
    Predictive Impact of RNF43 Mutations in Patients With Proficient Mismatch Repair/Microsatellite Stable BRAFV600E -Mutated Metastatic Colorectal Cancer Treated With Target Therapy or Chemotherapy
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  JCO Precision Oncology , No. 7 ( 2023-09)
    Details
    In: JCO Precision Oncology, American Society of Clinical Oncology (ASCO), , No. 7 ( 2023-09)
    Abstract: Target therapy (TT) with encorafenib plus cetuximab is a standard option in patients with BRAFV600E-mutated (mut) pretreated metastatic colorectal cancer (mCRC). Recently, mutations in RNF43, encoding a negative regulator of the WNT pathway, were associated with longer progression-free survival (PFS) and overall survival (OS) in patients with proficient mismatch repair/microsatellite stable (pMMR/MSS) BRAFV600E-mut mCRC treated with TT. Here, we explored the effect of RNF43 mutations on the efficacy of second-line TT versus standard chemotherapy (CT). METHODS A retrospective cohort of patients with pMMR/MSS BRAFV600E-mut tumors, available RNF43 mutational status, and treated with second-line TT or oxaliplatin- and/or irinotecan-based CT was analyzed. RESULTS One hundred thirty-two patients with pMMR/MSS BRAFV600E-mut mCRC were included. RNF43 was found mut in 34 (26%) cases. Among RNF43 mutants, TT was associated with longer PFS (7.7 v 3.0 months; P = .002) and higher overall response rate (ORR; 45% v 0%; P = .009) compared with CT. Conversely, among RNF43 wild-type (wt) patients, only a trend for longer PFS (4.5 v 3.7 months; P = .064) favoring TT, with no differences in ORR ( P = .14), was observed. After excluding 36 patients receiving TT in third line or beyond, a longer OS (19.4 v 10.1 months; P = .022) and a numerically OS advantage (10.6 v 6.6 months; P = .068) were reported for TT both in the RNF43-mut and in the RNF43 wt groups. However, no interaction effect was reported between RNF43 mutational status and treatment in ORR ( P interaction = .96), PFS ( P interaction = .13), and OS ( P interaction = .44). CONCLUSION Patients with pMMR/MSS BRAFV600E-mut mCRC achieve benefit from TT versus CT independently of RNF43 mutational status, although a higher magnitude of benefit from TT is observed in RNF43-mut tumors. These findings deserve confirmation in concluded and ongoing randomized trials.
    Type of Medium: Online Resource
    ISSN: 2473-4284
    URL: Article
    DOI: 10.1200/PO.23.00255
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
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  • 3
    Online Resource
    Online Resource
    Tumor mutational load, microsatellite instability and actionable mutations in metastatic colorectal cancer: Results from the TRIBE2 study.
    American Society of Clinical Oncology (ASCO) ; 2020
    In:  Journal of Clinical Oncology Vol. 38, No. 15_suppl ( 2020-05-20), p. 4077-4077
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 15_suppl ( 2020-05-20), p. 4077-4077
    Abstract: 4077 Background: In the TRIBE2 study molecularly unselected and untreated mCRC patients were randomized to receive FOLFOXIRI/bevacizumab (bev) followed by the same agents after disease progression (PD) or FOLFOX/bev followed by FOLFIRI/bev after PD. We performed a comprehensive NGS analysis of samples from randomized patients in order to investigate the prognostic impact of tumor mutational load (TML), its additional value with respect to the assessment of microsatellite instability (MSI), and the overall prevalence of potentially actionable alterations. Methods: Tumor DNA was obtained from formalin-fixed, paraffin-embedded blocks from primary tumors of 296 (44%) out of 679 randomized patients and underwent NGS analysis using the Caris MI TumorSeek panel, assessing 592 genes. TML was defined low, intermediate or high if 〈 7, 7-16 or 〉 16 mutations/Mb were found. MSI status was determined both by NGS and by IHC. Results: TML and MSI were successfully determined by NGS in 224 (76%) cases. NGS and IHC results were concordant in 221 (99%) cases. TML was low, intermediate or high in 56 (25%), 157 (70%) and 11 (5%) cases, respectively. When compared with TML low and intermediate tumors, TML high were more frequently right-sided (p = 0.013), mucinous (p 〈 0.001) and MSI-high (p 〈 0.001). TML high tumors were MSI-high or MSS in 8 (73%) and 3 (27%) cases, respectively. Two out of 3 TML high and MSS tumours showed a pathogenic POLE mutation (p.S459F and p.P286R). The other TML high, MSS and POLE wt tumor was dMMR at IHC (loss of MSH6 expression) and showed a pathogenic MSH6 mutation (p.F1040fs). As compared with low and intermediate TML, high TML was associated with longer PFS (median PFS: 17.3 vs 10.6; HR: 0.54 [95%CI: 0.35-1.09], p = 0.098) and OS (median OS: not reached vs 23.7: HR: 0.45 [95%CI:0-28-1.13] , p = 0.106). No interaction effect between TML and treatment arm was observed, and no difference between TML low and intermediate tumors was reported in terms of baseline characteristics and prognosis. Actionable alterations ( HER2 mutations [N = 2] and amplifications [N = 4] , KRAS G12C [N = 10] and BRAF V600E mutation [N = 39] ) were found in 55 (19%) out of 296 cases. No NTRK/ROS/ALK or MET amplification was found. Conclusions: TML high tumors are not limited to MSI-high ones but showed POLE or MSH6 somatic mutation and shower longer PFS and OS. No differences are reported between TML low and intermediate tumors. Molecular alterations predictive of benefit from targeted strategies currently available are detectable only in a small percentage of mCRCs.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2020.38.15_suppl.4077
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
    detail.hit.zdb_id: 2005181-5
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  • 4
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    Analysis of predictive and prognostic value of clinical and pathological factors in locally advanced rectal cancer (LARC) treated with neoadjuvant chemoradiotherapy (CRT): Bologna multidisciplinary rectal cancer group study (BMRG-B01-Study).
    American Society of Clinical Oncology (ASCO) ; 2013
    In:  Journal of Clinical Oncology Vol. 31, No. 4_suppl ( 2013-02-01), p. 421-421
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 31, No. 4_suppl ( 2013-02-01), p. 421-421
    Abstract: 421 Background: Preoperative fluoropyrimidine based CRT is standard treatment in LARC patients. The aim of this study was to evaluate prognostic and predictive role of clinical and pathological factors in this setting Methods: Between December 2001 and January 2012 we evaluated 149 pts with cT3-T4 N-/+ rectal adenocarcinoma located ≤12 cm from the anal margin. Preoperative CRT consisted of radiotherapy 50.4 Gy in 28 daily fractions + 5-fluorouracil or capecitabine +/- oxaliplatin. Rectal surgery with total mesorectal excision was performed 6-8 weeks after the end of neoadjuvant treatment. Pathological examination of surgical specimens included TRG according to the Dworak criteria. TS, EGFR, Ki-67, p53, Bcl-2, MLH1 and MSH2 were immunohistochemically determined in pre-treatment biopsies and surgical specimens. For immunohistochemistry evaluation serial sections of formalin-fixed, paraffin-embedded tissues were stained with specific antibodies using a biotin-free ready-to-use amplification system Results: After a median follow-up of 60 months (2-122) we observed 4.7% local recurrences, 12.7% distant recurrences, and 13.4% deaths. In surgical specimens TRG 1, 2, 3 and 4 were observed respectively in 22.5%, 35.3%, 25.6% and 16.6% of patients. ypN and TRG were independent prognostic factors of DFS (p=0.020, p=0.027). CRM and TRG were independent prognostic factors of OS (p=0.016, p=0.010). High pre-treatment biopsy expression of TS was associated with poor TRG (0-1) (p=0.007); high biopsy expression of Ki-67 was associated with good TRG (2-4) (p=0.039); decrease between pre-treatment biopsy and surgical specimen of Ki-67 (Δ Ki-67 ≥ 0) was associated with good TRG (2-4) (p=0.02). Decrease in Ki-67 (Δ Ki-67 ≥ 0) was associated with good DFS (p=0.011) and confirmed by multivariate analysis as an independent prognostic factor (p=0.035). Conclusions: In our analysis ypN, CRM and TRG were independent prognostic factors; baseline expression of TS, Ki-67 and decrease in Ki-67 were predictive of TRG; decrease in Ki-67 was an independent prognostic factor of DFS.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2013.31.4_suppl.421
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2013
    detail.hit.zdb_id: 2005181-5
    Location Call Number Limitation Availability
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  • 5
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    Online Resource
    Exploring the prognostic and predictive impact of genomic loss of heterozygosity (LOH) in patients with metastatic colorectal cancer (mCRC).
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. 3576-3576
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 3576-3576
    Abstract: 3576 Background: Genomic LOH consists in the loss of chromosomal regions and is associated with the homologous recombination repair (HRR) system deficiency (dHRR). In ovarian cancer, LOH-high predicts benefit from platinum-based chemotherapy and PARP inhibitors. In mCRC, the role of LOH has been poorly investigated. Methods: An NGS-based assay (FoundationOne CDx; Foundation Medicine, Inc. Cambrige, MA) was used to determine the percentage of genomic LOH and the presence of pathogenetic mutations in HRR-related genes in archival chemo-naïve tumor tissues of mCRC patients included in a real-world registry and in the AtezoTRIBE (NCT03721653) and AVETRIC (NCT04513951) studies. Both these trials assessed the combination of an anti-PDL1 (atezolizumab or avelumab) with the triplet FOLFOXIRI plus bevacizumab or cetuximab. The prespecified cut-off of ≥14.08 for LOH-high described for mCRC (Sokol et al., JCO Precis Oncol 2020) was adopted. Tumors with at least one biallelic alteration in any of the 27 genes involved in the HRR pathway (Riaz et al., Nat Commun 2017) included in the FoundationOne CDx panel (BARD1, BRCA1, BRCA2, BRIP1, MRE11A, NBN, PALB2, RAD51, RAD51B, RAD51C, RAD51D, RAD52, RAD54L, RBBP8, XRCC2, ABL1, ATM, ATR, BAP1, CDK12, DNMT3A, ERCC4, FANCA, FANCC, FANCG, FANCL, PARP1) were defined dHRR. Results: Overall, 196 samples were analysed. None of 7 MSI-H tumors were classified as LOH-high. Fourteen (7%) and 6 (3%) of 189 MSS tumors were classified as LOH-high and dHRR, respectively. In particular, in LOH-high subgroup, 3 (21%) tumors were defined dHRR, while 3 (50%) tumors were classified LOH-high among dHRR tumors. LOH-high tumors were more frequently BRAF mutated (p = 0.019) and dHRR (p = 0.006) compared to LOH-low. Among patients receiving triplet chemotherapy +/- biologic agent alone (N = 55) or with an anti-PDL1 (N = 58), an interaction effect was shown between the effect of the addition of the checkpoint inhibitor and LOH with higher benefit in the LOH-high subgroup (N = 10) in terms of both PFS (p interaction = 0.002) and OS (p interaction 〈 0.001). In the cohort of patients not receiving the anti-PDL1, longer PFS was observed in patients with LOH-low (N = 125) respect to LOH-high (N = 6) tumors (12.1 vs 5.1 months, HR: 0.11, 95%CI: 0.04-0.26, p 〈 0.001). No differences in PFS or OS were reported between patients treated with first-line oxaliplatin- (N = 40) vs irinotecan-based doublets (N = 25) or with the triplet FOLFOXIRI (N = 55) vs doublets (N = 65) according to LOH status. No prognostic or predictive impact of HRR deficiency was shown. Conclusions: In MSS mCRC, LOH-high was associated with biallelic alterations in the HRR system, worse prognosis and higher benefit from the addition of anti-PDL1 agents to chemotherapy. Considering the low number of LOH-high tumors in our study, these results deserve confirmation in larger cohorts.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.16_suppl.3576
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
    Location Call Number Limitation Availability
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  • 6
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    A phase II study of capecitabine plus concomitant radiation therapy followed by durvalumab (MEDI4736) as preoperative treatment in rectal cancer: PANDORA study final results.
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 17_suppl ( 2022-06-10), p. LBA3513-LBA3513
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 17_suppl ( 2022-06-10), p. LBA3513-LBA3513
    Abstract: LBA3513 Background: The combination of capecitabine plus long course radiotherapy (RT) is the standard preoperative therapy in cT3-4 cN+ rectal cancer. pathologic complete remission (pCR) can be considered as surrogate endpoint of efficacy of treatment in terms of disease-free survival (DFS). Preclinical data points heavily toward a strong synergy between RT and immune treatments. Methods: This is a prospective phase II, open label, single arm, multicentre study in patient with locally advanced rectal cancer who receive standard concomitant CT/RT therapy (825 mg/m2 twice daily capecitabine every day and 5040 cGy radiotherapy for 5 days per week for 5 weeks) followed by durvalumab (1500 mg Q4W for 3 administrations). Surgery is performed after 10-12 weeks from neoadjuvant therapy. The primary endpoint is the proportion of pCRs after at least 1 cycle of durvalumab; secondary endpoints are the proportion of clinical complete remissions (cCRs) after at least 1 cycle of durvalumab, the proportion of adverse and serious adverse events (NCI CTCAE v5.0). The sample size has been estimated by using the optimal Simon’s two-stage design assuming a null pCR proportion of 0.15 and an alternative pCR percentage of 0.30 (alpha = 0.05, power = 0.80). If more than 4 pCRs were observed in the first 19 enrolled patients, 36 additional patients were to be accrued for a total of 55 evaluable patients. The null hypothesis is rejected if ≥ 13 pCRs are observed in 55 patients. Results: Between November 2019 and August 2021, 60 patients were accrued, of which 55 were evaluable for study objectives. Fifty-two of 55 treated patients received all 3 infusions of durvalumab. After treatment, a clinical response percentage of 81.8% was observed; 3 patients had progression of disease due to local and/or metastases before surgical intervention. Eighteen patients achieved complete pathological response (32.7%), confirmed by central revision. Near complete regression, moderate and minimal regression were observed in 14 (25.5%), 9 (16.4%) and 11 (20.0%) patients respectively. Regarding toxicity, 23 patients (41.8%) had adverse events (AEs) related to durvalumab treatment. Two patients (1.8%) discontinued durvalumab for toxicity. Grade 3 AEs occurred in 4 (7.3%) patients (diarrhea, skin toxicity, transaminase increase, lipase increase and pancolitis). No Grade 4 toxicity was observed. In 20 patients (36.4%) G1-2 AEs related to durvalumab were observed. The most common were endocrine toxicity (hyper/hypo-thyroidism), dermatologic toxicity (skin rash) and gastrointestinal toxicity (transaminase increase, nausea, diarrhea, constipation). Conclusions: This study met its primary endpoint showing a promising activity of neoadjuvant chemo-radiotherapy plus durvalumab in terms of pCR rate and a safe toxicity profile. Clinical trial information: NCT04083365.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.17_suppl.LBA3513
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
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