Content uploaded by Michael H Roehrl
Author content
All content in this area was uploaded by Michael H Roehrl on Aug 18, 2020
Content may be subject to copyright.
O-17 A TNM-Immune (TNM-I) classification staging system for predicting
survival in colon cancer in a multicenter international SITC study
B. Mlecnik
1
, C. Bifulco
2
, F. Marliot
3
, A. Lugli
4
, I. Nagtegaal
5
, A. Hartmann
6
,
M. Van den Eynde
7
, M. Roehrl
8
, P. Ohashi
9
, E. Zavadova
10
, T. Torigoe
11
, P. Patel
12
,
Y. Wang
13
, Y. Kawakami
14
, F. Hermitte
15
, F. Marincola
16
, P. Ascierto
17
, B. Fox
18
,
F. Pagès
3
, J. Galon
19
1
INSERM, Paris, France;
2
Earle A. Chiles Research Institute at Robert W. Franz Cancer
Center, Providence, Portland, United States;
3
Centre Université de Paris, HEGP, APHP,
Paris, France;
4
University of Bern, Bern, Switzerland;
5
Department of Pathology,
Radboud UMC, Nijmegen, Netherlands;
6
University of Erlangen-Nuernberg, Erlangen,
Germany;
7
Université Catholique de Louvain, Brussels, Belgium;
8
Memorial Sloan
Kettering Cancer Center, New York, United States;
9
The Princess Margaret Cancer
Centre, Toronto, Canada;
10
Department of Oncology, First Faculty of Medicine, Charles
University, Prague, Czech Republic;
11
Department of Pathology, Sapporo Medical
University School of Medicine, Sapporo, Japan;
12
The Gujarat Cancer and Research
Institute, Ahmedabad, India;
13
Health Science Center of Xi’an Jiaotong University,
Xian, China;
14
Keio University School of Medicine, Tokyo, Japan;
15
HalioDx, Marseille,
France;
16
Abbvie Inc, Mettawa, United States;
17
National Tumour Institute Fondazione
G. Pascale, Naples, Italy;
18
Earle A. Chiles Research Institute, Providence Cancer
Institute, Portland, OR, Portland, United States;
19
Laboratory of Integrative Cancer
Immunology, INSERM, Paris, France
Background: The present study was performed to evaluate the predictive capacity of
the TNM-Immune (TNM-I) classification staging system vs. the 8th edition of the
American Joint Committee on Cancer (AJCC) and the Union for International Cancer
Control (UICC) tumor-node-metastasis (TNM8) staging system for survival of patients
with colon cancer.
Methods: Data of eligible patients from the Society-for-Immunotherapy-of-Cancer
(SITC) international-consortium from 13 countries were evaluated for the consensus
Immunoscore in 3539 patients with AJCC/UICC-TNM stages I-III colon cancer. The
primary-endpoint time-to-recurrence (TTR) and secondary-endpoint overall-survival
(OS) were evaluated for 2650 patients with complete TNM staging and Immunoscore
information. The consensus Immunoscore was predefined and previously published
(Pages et al. Lancet 2018), and TNM-I categories (IA to IIID) were performed based on
TNM8 plus consensus Immunoscore categories.
Results: A total of 1737 (64.8%) patients presented stage migration, including 1495
(55.8%) migrating to a lower stage and 242 (9.0%) to a higher stage. In TNM8 stage
IIIB, patients migrated to all possible TNM-I stages from IA to IIID. A total of 563 Stage
IIIB (67.0%) patients presented stage migration, including 181 (32.1%) migrating to a
lower stage and 196 (34.8%) to a higher stage. TNM-I Hazard ratio for TTR between
TNM-I stage IA and IIID was HR¼16.9 (95%CI 7.75-36.83), in contrast TNM8 TTR
between IA and IIIC was only HR¼12.77 (95%CI 7.99-20.4), all P<0.0001. TNM-I
Hazard ratio for OS between TNM-I stage IA and IIID was HR¼5.95 (95%CI 3.17-
11.19), in contrast, TNM8 OS between IA and IIIC was only HR¼3.16 (95%CI 2.38-
4.18), all P<0.0001. The TNM8 staging system exhibited prognostic discrepancies in
discriminating stage IIB and IIC and between IIC and IIIA on survival curves from TTR
and OS, which were improved in the TNM-I staging system. In cox multivariate
analysis, the relative contribution of TNM-I was 90.3% in comparison to gender,
sidedness, MSI, grade of differentiation, mucinous colloid, VELIPI. The TNM-I had a
better predictive capability of survival, as evidenced by higher likelihood ratio scores,
and smaller AIC values for TNM-I compared with those for TNM8 edition.
Conclusion: Therefore, the present study showed the importance of immuno-pa-
thology and demonstrated that the TNM-Immune (TNM-I) classification staging sys-
tem is superior (log-likelihood ratio test P<0.0001) to the 8th edition of the AJCC/
UICC-TNM staging system in predicting the TTR and OS of patients with colon cancer.
Legal entity responsible for the study: The authors.
Funding: French National Institute of Health and Medical Research, the LabEx
Immuno-oncology, the Transcan ERAnet Immunoscore European project, Association
pour la Recherche contre le Cancer, CARPEM, AP-HP, Institut National du Cancer,
Italian Association for Cancer Research, national grants and the Society for Immu-
notherapy of Cancer.
Disclosure: The first author has declared no conflicts of interest; no disclosure provided for the
presenting author.
https://doi.org/10.1016/j.annonc.2020.04.070
O-18 Tumor mutational load, microsatellite instability, BRCAness, and
actionable alterations in metastatic colorectal cancer: Results from
the TRIBE2 study
C. Antoniotti
1
, D. Rossini
1
, F. Marmorino
1
, S. Lonardi
2
, F. Corti
3
, R. Moretto
4
,
C. Ugolini
5
, T. Latiano
6
, M. Giordano
7
, E. Tamburini
8
, A. Passardi
9
, D. Santini
10
,
A. Zaniboni
11
, G. Aprile
12
, R. Bordonaro
13
, G. Zucchelli
1
, V. Conca
1
, G. Fontanini
7
,
H. Lenz
14
, A. Falcone
1
, M. Korn
15
, C. Cremolini
16
1
Department of Translational Research and New Technologies in Medicine and Sur-
gery, University of Pisa, Pisa, Italy;
2
Medical Oncology Unit 1, Department of Clinical
and Experimental Oncology, Istituto Oncologico Veneto eIRCCS, Padua, Italy;
3
Fon-
dazione IRCCS Istituto Nazionale Tumori, Milano, Italy;
4
Department of Oncology,
University Hospital of Pisa, Pisa, Italy;
5
Unit of Pathological Anatomy, Azienda
Ospedaliero-Universitaria Pisana, Pisa, Italy;
6
Division of Medical Oncology, Fonda-
zione IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy;
7
Depart-
ment of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa,
Pisa, Italy;
8
Oncology Unit, Ospedale degli Infermi, Rimini, Italy;
9
Department of
Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori
(IRST) IRCCS, Meldola, Italy;
10
Department of Medical Oncology, University Campus
Biomedico, Roma, Italy;
11
Medical Oncology Unit, Poliambulanza Foundation, Brescia,
Italy;
12
Department of Oncology, University and General Hospital, Udine, Italy;
13
Medical Oncology Unit, ARNAS Garibaldi, Catania, Italy;
14
University of Southern
California, Los Angeles, United States;
15
Caris Life Sciences, Phoenix, United States;
16
Azienda Ospedaliero Universitaria Pisana, Pisa, Italy
Background: In the TRIBE2 study, molecularly unselected and untreated mCRC pa-
tients were randomized to receive FOLFOXIRI/bevacizumab (bev) followed by the
same agents after disease progression (PD) or FOLFOX/be v 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. We also investigated
the prevalence and the prognostic impact of the so-called “BRCAness”alterations,
whose prevalence and prognostic impact in mCRC are currently unknown.
Methods: Tumor DNA was obtained from formalin-fixed, paraffin-embedded blocks
from primary tumors of 296 (44%) of 679 randomized patients, and underwent NGS
analysis using the Caris MI TumorSeek panel, assessing 592 genes. TML was defined as
low, intermediate, or high based on finding 16 mutations/Mb. MSI status was
determined both by NGS and by IHC. BRCAness group was defined by the presence of
pathogenic alterations in at least one of the following genes: BRCA1/2, PALB2, RAD50,
RAD51, ATM, ATR, FANC(A-C- D2-E-F-G-L), EMSY, BARD1, BRIP1, CHEK1, CHEK2,
MRE11, BLM, NBN, or WNR.
Results: TML and MSI were 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. TML-high tumors were MSI-high or
MSS in 8 (73%) and 3 (27%) cases, respectively. Two of 3 TML-high and MSS tumors
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 ¼.098) and OS (median OS: not reached vs 23.7; HR :0.45 [95%
CI: 0-28-1.13], P ¼.106). No interaction effect between TML and treatment arm was
observed, and no difference between TML-low and -intermediate tumors was re-
ported in terms of baseline characteristics and prognosis. Potentially actionable al-
terations (BRAF V600E and KRAS G12C mutations, HER2 mutations/amplification)
were found in 55 (19%) of 296 cases. No NTRK/ROS/ALK or MET amplifications were
found. At least one BRCAness alteration was reported in 40 (14%) of 296 patients. In
all, 56 different BRCAness alterations were found, with ATM (21/56, 38%) and BRCA1/
2 (13/56, 23%) being the most frequently mutated genes. Longer PFS (13.4 vs 10.6
months; HR: 0.67 [95% CI: 0.48-0.93], P ¼.032) and OS (30.1 vs 23.9, HR: 0.66 [95%
CI: 0.43-1.02], P ¼.062) were observed in the BRCAness group. No interaction effect
between BRCAness and treatment arm was reported.
Conclusion: TML-high tumors are not limited to MSI-high, but may also present POLE
or MSH6 somatic mutation and show improved outcomes. No differences are re-
ported between TML-low and -intermediate tumors. BRCAness alterations are asso-
ciated with better prognosis. Molecular alterations predictive of benefit from targeted
strategies are detectable in a small percentage of mCRCs.
Legal entity responsible for the study: The author.
Funding: GONO Foundation.
Disclosure: The presenting author has declared no conflicts of interest.
https://doi.org/10.1016/j.annonc.2020.04.071
Annals of Oncology abstracts
S238 Volume 31 -Issue S3 -2020