Improving selection of patients with metastatic colorectal cancer to benefit from
      cetuximab based on KIR genotypes

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Abstract

Aim

Cetuximab is a standard-of-care treatment for KRAS wild-type metastatic colorectal cancer (mCRC), but it may also be effective in a subgroup of KRAS mutant patients by its immunomodulatory activity. Here, we explore if KIR (killer cell immunoglobulin-like receptor) genotyping can provide a significant added value in the clinical outcome of patients with KRAS mutant mCRC based on cetuximab treatment.

Methods

We included 69 patients with histologically confirmed mCRC and KRAS mutation, positive EGFR expression, and Eastern Cooperative Oncology Group performance status ≤2. Based on KIR gene content, haplotype (A or B) was defined and genotypes (AA or Bx) were grouped for each patient.

Results

We demonstrated with new evidence the immunomodulatory activity of cetuximab in patients with KRAS mutant mCRC. Patients with homozygous genotypes (AA or BB) showed shorter 12-month progression-free survival (PFS12) and poorer overall survival (OS) than those with heterozygotes (AB). Moreover, multivariate analysis confirmed stratification of patients based on genotype was an independent marker of PFS12 (HR 2.16) and the centromeric and telomeric distribution of KIRs was an independent predictor of both PFS12 (HR 2.26) and OS (HR 1.93) in patients with mCRC with KRAS mutation treated with cetuximab.

Conclusions

Selection of patients with mCRC based on their KIR genotypes opens a therapeutic opportunity for patients with KRAS mutation, and it should be tested in clinical trials in comparison with other alternatives with scarce benefit.

Trial registration number

NCT01450319, EudraCT 2010-023580-18.

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Most cited references 55

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Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries

Ahmedin Jemal, Lindsey A Torre, Rebecca Siegel … (2018)

This article provides a status report on the global burden of cancer worldwide using the GLOBOCAN 2018 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer, with a focus on geographic variability across 20 world regions. There will be an estimated 18.1 million new cancer cases (17.0 million excluding nonmelanoma skin cancer) and 9.6 million cancer deaths (9.5 million excluding nonmelanoma skin cancer) in 2018. In both sexes combined, lung cancer is the most commonly diagnosed cancer (11.6% of the total cases) and the leading cause of cancer death (18.4% of the total cancer deaths), closely followed by female breast cancer (11.6%), prostate cancer (7.1%), and colorectal cancer (6.1%) for incidence and colorectal cancer (9.2%), stomach cancer (8.2%), and liver cancer (8.2%) for mortality. Lung cancer is the most frequent cancer and the leading cause of cancer death among males, followed by prostate and colorectal cancer (for incidence) and liver and stomach cancer (for mortality). Among females, breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death, followed by colorectal and lung cancer (for incidence), and vice versa (for mortality); cervical cancer ranks fourth for both incidence and mortality. The most frequently diagnosed cancer and the leading cause of cancer death, however, substantially vary across countries and within each country depending on the degree of economic development and associated social and life style factors. It is noteworthy that high-quality cancer registry data, the basis for planning and implementing evidence-based cancer control programs, are not available in most low- and middle-income countries. The Global Initiative for Cancer Registry Development is an international partnership that supports better estimation, as well as the collection and use of local data, to prioritize and evaluate national cancer control efforts. CA: A Cancer Journal for Clinicians 2018;0:1-31. © 2018 American Cancer Society.

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Controlling natural killer cell responses: integration of signals for activation and inhibition.

Sumati Rajagopalan, S. H. Kim, Eric Long … (2012)

Understanding how signals are integrated to control natural killer (NK) cell responsiveness in the absence of antigen-specific receptors has been a challenge, but recent work has revealed some underlying principles that govern NK cell responses. NK cells use an array of innate receptors to sense their environment and respond to alterations caused by infections, cellular stress, and transformation. No single activation receptor dominates; instead, synergistic signals from combinations of receptors are integrated to activate natural cytotoxicity and cytokine production. Inhibitory receptors for major histocompatibility complex class I (MHC-I) have a critical role in controlling NK cell responses and, paradoxically, in maintaining NK cells in a state of responsiveness to subsequent activation events, a process referred to as licensing. MHC-I-specific inhibitory receptors both block activation signals and trigger signals to phosphorylate and inactivate the small adaptor Crk. These different facets of inhibitory signaling are incorporated into a revocable license model for the reversible tuning of NK cell responsiveness.

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Author and article information

Journal

Journal ID (nlm-ta): J Immunother Cancer

Journal ID (iso-abbrev): J Immunother Cancer

Journal ID (hwp): jitc

Journal ID (publisher-id): jitc

Title: Journal for Immunotherapy of Cancer

Publisher: BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )

ISSN (Electronic): 2051-1426

Publication date Collection: 2021

Publication date (Electronic): 8 April 2021

Volume: 9

Issue: 4

Electronic Location Identifier: e001705

Affiliations

[1 ]departmentImmunology Unit , Reina Sofia University Hospital , Cordoba, Andalucía, Spain

[2 ]departmentOncology, Translational Oncology Division , Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz , Madrid, Madrid, Spain

[3 ]departmentMedical Oncology , Reina Sofia University Hospital , Cordoba, Andalucía, Spain

Author notes

[Correspondence to ] Dr Arancha Cebrián Aranda; arancha.cebrian@ 123456oncohealth.eu ; Dr Laura del Puerto-Nevado; lpuerto@ 123456oncohealth.eu ; Dr Jesús García-Foncillas; jesus.garciafoncillas@ 123456oncohealth.eu

Author information

Arancha Cebrián Aranda http://orcid.org/0000-0002-6260-1376

Article

Publisher ID: jitc-2020-001705

DOI: 10.1136/jitc-2020-001705

PMC ID: 8039212

PubMed ID: 33833048

SO-VID: 9bd4808f-a87b-41ea-a2c8-c1b5a0fb5aee

License:

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.

History

Date accepted : 06 March 2021

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100009945, Merck KGaA;

Award ID: 2010-023580-18, date: 05-06-2014

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Keywords: biomarkers,tumor,natural killer t-cells,translational medical research,antibodies,neoplasm

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Keywords: biomarkers, tumor, natural killer t-cells, translational medical research, antibodies, neoplasm

Improving selection of patients with metastatic colorectal cancer to benefit from cetuximab based on KIR genotypes

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Most cited references 55

Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries

Metastatic colorectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.

Controlling natural killer cell responses: integration of signals for activation and inhibition.

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