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      Clinical significance of BIM deletion polymorphism in chemoradiotherapy for non‐small cell lung cancer

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          Abstract

          The standard treatment for locally advanced non‐small cell lung cancer (NSCLC) is chemoradiotherapy (CRT) followed by anti‐programmed cell death‐ligand 1 (anti‐PD‐L1) treatment. BIM deletion polymorphism induces the suppression of apoptosis resulting from epidermal growth factor (EGFR)‐tyrosine kinase inhibitors in EGFR‐mutated NSCLC patients. We aimed to examine the effects of BIM polymorphism on CRT and anti‐PD‐L1/PD‐1 treatment in NSCLC patients. In this retrospective study of 1312 patients with unresectable NSCLC treated at Higashi‐Hiroshima Medical Center and Hiroshima University Hospital between April 1994 and October 2019, we enrolled those who underwent CRT or chemotherapy using carboplatin + paclitaxel or cisplatin + vinorelbine, or anti‐PD‐L1/PD‐1 treatment. Of 1312 patients, 88, 80, and 74 underwent CRT, chemotherapy, and anti‐PD‐L1/PD‐1 treatment, respectively, and 17.0%, 15.2% and 17.6% of these patients showed BIM polymorphism. Among patients receiving CRT, the progression‐free survival was significantly shorter in those with BIM deletion than in those without. In the multivariate analyses, BIM polymorphism was an independent factor of poor anti‐tumor effects. These results were not observed in the chemotherapy and anti‐PD‐L1/PD‐1 treatment groups. In in vitro experiments, BIM expression suppression using small interfering RNA in NSCLC cell lines showed a significantly suppressed anti‐tumor effect and apoptosis after irradiation but not chemotherapy. In conclusion, we showed that BIM polymorphism was a poor‐predictive factor for anti‐tumor effects in NSCLC patients who underwent CRT, specifically radiotherapy. In the implementation of CRT in patients with BIM polymorphism, we should consider subsequent treatment, keeping in mind that CRT may be insufficient.

          Abstract

          We showed that progression‐free survival and overall survival durations were significantly shorter in the CRT‐treated NSCLC patients with BIM polymorphism than in those without. Our findings indicate that BIM polymorphism is associated with the efficacy of radiotherapy but not chemotherapy in patients with CRT.

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          Cancer statistics, 2019

          Rebecca Siegel, Kimberly D Miller, Ahmedin Jemal (2019)
          Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States and compiles the most recent data on cancer incidence, mortality, and survival. Incidence data, available through 2015, were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data, available through 2016, were collected by the National Center for Health Statistics. In 2019, 1,762,450 new cancer cases and 606,880 cancer deaths are projected to occur in the United States. Over the past decade of data, the cancer incidence rate (2006-2015) was stable in women and declined by approximately 2% per year in men, whereas the cancer death rate (2007-2016) declined annually by 1.4% and 1.8%, respectively. The overall cancer death rate dropped continuously from 1991 to 2016 by a total of 27%, translating into approximately 2,629,200 fewer cancer deaths than would have been expected if death rates had remained at their peak. Although the racial gap in cancer mortality is slowly narrowing, socioeconomic inequalities are widening, with the most notable gaps for the most preventable cancers. For example, compared with the most affluent counties, mortality rates in the poorest counties were 2-fold higher for cervical cancer and 40% higher for male lung and liver cancers during 2012-2016. Some states are home to both the wealthiest and the poorest counties, suggesting the opportunity for more equitable dissemination of effective cancer prevention, early detection, and treatment strategies. A broader application of existing cancer control knowledge with an emphasis on disadvantaged groups would undoubtedly accelerate progress against cancer.
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            Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer.

            Scott J Antonia, Augusto Villegas, Davey Daniel … (2017)
            Background Most patients with locally advanced, unresectable, non-small-cell lung cancer (NSCLC) have disease progression despite definitive chemoradiotherapy (chemotherapy plus concurrent radiation therapy). This phase 3 study compared the anti-programmed death ligand 1 antibody durvalumab as consolidation therapy with placebo in patients with stage III NSCLC who did not have disease progression after two or more cycles of platinum-based chemoradiotherapy. Methods We randomly assigned patients, in a 2:1 ratio, to receive durvalumab (at a dose of 10 mg per kilogram of body weight intravenously) or placebo every 2 weeks for up to 12 months. The study drug was administered 1 to 42 days after the patients had received chemoradiotherapy. The coprimary end points were progression-free survival (as assessed by means of blinded independent central review) and overall survival (unplanned for the interim analysis). Secondary end points included 12-month and 18-month progression-free survival rates, the objective response rate, the duration of response, the time to death or distant metastasis, and safety. Results Of 713 patients who underwent randomization, 709 received consolidation therapy (473 received durvalumab and 236 received placebo). The median progression-free survival from randomization was 16.8 months (95% confidence interval [CI], 13.0 to 18.1) with durvalumab versus 5.6 months (95% CI, 4.6 to 7.8) with placebo (stratified hazard ratio for disease progression or death, 0.52; 95% CI, 0.42 to 0.65; P<0.001); the 12-month progression-free survival rate was 55.9% versus 35.3%, and the 18-month progression-free survival rate was 44.2% versus 27.0%. The response rate was higher with durvalumab than with placebo (28.4% vs. 16.0%; P<0.001), and the median duration of response was longer (72.8% vs. 46.8% of the patients had an ongoing response at 18 months). The median time to death or distant metastasis was longer with durvalumab than with placebo (23.2 months vs. 14.6 months; P<0.001). Grade 3 or 4 adverse events occurred in 29.9% of the patients who received durvalumab and 26.1% of those who received placebo; the most common adverse event of grade 3 or 4 was pneumonia (4.4% and 3.8%, respectively). A total of 15.4% of patients in the durvalumab group and 9.8% of those in the placebo group discontinued the study drug because of adverse events. Conclusions Progression-free survival was significantly longer with durvalumab than with placebo. The secondary end points also favored durvalumab, and safety was similar between the groups. (Funded by AstraZeneca; PACIFIC ClinicalTrials.gov number, NCT02125461 .).
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              Regulation of apoptosis in health and disease: the balancing act of BCL-2 family proteins

              Rumani Singh, Anthony Letai, Kristopher A Sarosiek (2019)
              The loss of vital cells within healthy tissues contributes to the development, progression and treatment outcomes of many human disorders, including neurological and infectious diseases as well as environmental and medical toxicities. Conversely, the abnormal survival and accumulation of damaged or superfluous cells drive prominent human pathologies such as cancers and autoimmune diseases. Apoptosis is an evolutionarily conserved cell death pathway that is responsible for the programmed culling of cells during normal eukaryotic development and maintenance of organismal homeostasis. This pathway is controlled by the BCL-2 family of proteins, which contains both pro-apoptotic and pro-survival members that balance the decision between cellular life and death. Recent insights into the dynamic interactions between BCL-2 family proteins and how they control apoptotic cell death in healthy and diseased cells have uncovered novel opportunities for therapeutic intervention. Importantly, the development of both positive and negative small-molecule modulators of apoptosis is now enabling researchers to translate the discoveries that have been made in the laboratory into clinical practice to positively impact human health.
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                Author and article information

                Contributors
                Takeshi Masuda:
                ORCID: https://orcid.org/0000-0003-3557-0049
                ta-masuda@hiroshima-u.ac.jp
                Journal
                Journal ID (nlm-ta): Cancer Sci
                Journal ID (iso-abbrev): Cancer Sci
                Journal ID (doi): 10.1111/(ISSN)1349-7006
                Journal ID (publisher-id): CAS
                Title: Cancer Science
                Publisher: John Wiley and Sons Inc. (Hoboken )
                ISSN (Print): 1347-9032
                ISSN (Electronic): 1349-7006
                Publication date (Electronic): 12 November 2020
                Publication date (Print): January 2021
                Volume: 112
                Issue: 1 ( doiID: 10.1111/cas.v112.1 )
                Pages: 369-379
                Affiliations
                [ 1 ] Department of Molecular and Internal Medicine Graduate School of Biomedical and Health Sciences Hiroshima University Hiroshima Japan
                [ 2 ] Department of Respiratory Internal Medicine Hiroshima University Hospital Hiroshima Japan
                [ 3 ] Department of Respiratory Internal Medicine Higashihiroshima Medical Center Higashihiroshima Japan
                [ 4 ] Department of Emergency and Critical Care Medicine Graduate School of Biomedical and Health Sciences Hiroshima University Hiroshima Japan
                [ 5 ] Department of Physical Analysis and Therapeutic Sciences Hiroshima University Hiroshima Japan
                Author notes
                [*] [* ] Correspondence

                Takeshi Masuda, Department of Respiratory Internal Medicine, Hiroshima University Hospital, 1‐2‐3 Kasumi, Minami‐ku, Hiroshima 734‐8551, Japan.

                Email: ta-masuda@ 123456hiroshima-u.ac.jp

                Author information
                https://orcid.org/0000-0003-3557-0049
                https://orcid.org/0000-0003-4922-5334
                Article
                Publisher ID: CAS14711
                DOI: 10.1111/cas.14711
                PMC ID: 7780054
                PubMed ID: 33103296
                SO-VID: 54ccf320-636a-411c-9927-a1667c1ae8c9
                Copyright © © 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.
                License:

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                Date received : 20 July 2020
                Date revision received : 12 October 2020
                Date accepted : 19 October 2020
                Page count
                Figures: 7, Tables: 4, Pages: 11, Words: 6108
                Categories
                Subject: Original Article
                Subject: Clinical Research
                Custom metadata
                source-schema-version-number 2.0
                cover-date January 2021
                details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:5.9.6 mode:remove_FC converted:04.01.2021

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: bim,chemoradiotherapy,chemotherapy,non‐small cell lung cancer,radiotherapy
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: bim, chemoradiotherapy, chemotherapy, non‐small cell lung cancer, radiotherapy

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